Olutasidenib Monotherapy, Combination Active in IDH1-Mutated AML

By Cecilia Brown - January 3, 2023

Olutasidenib, alone or in combination with azacitidine, had “meaningful clinical activity” in patients with IDH1-mutated acute myeloid leukemia (AML), according to a recent study.

Justin M. Watts, MD, of the University of Miami Sylvester Comprehensive Cancer Center, and colleagues conducted the research and published their findings in the Lancet Haematology.

Dr. Watts and colleagues conducted the phase I/II study to assess olutasidenib, a potent, selective, oral, small-molecule inhibitor of mutant IDH1. In phase I of the study, the researchers evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the drug as monotherapy or combined with azacitidine in patients with IDH1-mutated AML or myelodysplastic syndrome (MDS).

The phase I/II multicenter open-label clinical trial included 78 adult patients with mutated IDH1 who had AML or intermediate, high, or very high-risk MDS. Researchers conducted the study at 18 sites in the United States, Australia, France, and Spain.

Patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). Patients received oral olutasidenib in doses of 150 mg once daily, 150 mg twice daily, and 300 mg once daily. Those undergoing combination therapy received azacitidine 75 mg/m2 subcutaneously or intravenously daily for seven days, followed by 21 days off. The median follow-up time was 8.3 months for patients receiving olutasidenib monotherapy and 10.1 months for those receiving combination therapy.

Olutasidenib monotherapy led to an overall response rate (ORR) of 41% in patients with relapsed/refractory AML, while olutasidenib plus azacitidine led to an ORR of 46% in these patients. In treatment-naïve patients with AML, the ORR was 25% for those receiving monotherapy and 77% in those receiving combination therapy.

The researchers did not report any dose-limiting toxicities in the dose-escalation cohorts and determined olutasidenib 150 mg twice daily would be the recommended phase II dose on “the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity,” they wrote.

The most common grade 3 to grade 4 treatment-emergent adverse events occurring with olutasidenib monotherapy were thrombocytopenia in 28% of patients, febrile neutropenia in 22%, and anemia in 22%. In patients receiving combination therapy, the most common grade 3 to 4 treatment-emergent adverse events were thrombocytopenia in 41% of patients, febrile neutropenia in 28%, neutropenia in 28%, and anemia in 20%.

Of the patients receiving monotherapy, 34% died, while 20% of the patients receiving combination therapy died. Disease progression was the most common reason for death. No deaths were considered related to the study drug, according to the study’s authors.

“Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukemia,” Dr. Watts and colleagues concluded. “The results of this phase I study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies.”


Watts JM, Baer MR, Yang J, et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol. 2023;10(1):e46-e58.

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