Olutasidenib demonstrates efficacy in patients with relapsed/refractory IDH1 mutant AML

First results of a phase 2 study demonstrated durable complete remissions in patients with relapsed/refractory IDH1 mutant acute myeloid leukaemia (AML) after monotherapy with IDH1 inhibitor olutasidenib.

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism, epigenetic regulation, redox states, and DNA repair. IDH1 mutations are causal in the development and/or progression of various types of cancer due to the supraphysiological production of D-2-hydroxyglutarate (2HG). IDH1 mutations occur in 6–10% of AML patients [1]. Olutasidenib is a highly potent selective and orally active inhibitor of IDH1 mutants, inhibiting 2HG over-production.

The phase 2, multicohort 2102M 101 trial (NCT02719574) is evaluating olutasidenib as a single agent and in combination with azacitidine in IDH1 mutant AML patients. Dr Stéphane de Botton (Institute Gustave Roussy, France) presented interim results from cohort 1 in which 153 patients with relapsed or refractory AML received olutasidenib alone at the dose of 150 milligrams twice daily over continuous 28-day cycles [2]. The primary endpoint was complete remission (CR) plus complete remission with partial haematological recovery (CRh). Additional endpoints included overall response rate, duration of response, overall survival, transfusion independence, and safety.

At a median duration of treatment of 5.5 months, a total of 123 patients were evaluable for efficacy. The CR+CRh rate was 33%, including 30% of patients achieving CR. Composite CR (CR+CRh+CR with incomplete recovery) was 45%. The median duration of CR+CRh was not reached. The median duration of overall response was 11.7 months. The median overall survival for CR+CRh patients was not reached. For non-CR+CRh patients, the median overall survival was 15.0 months, for non-responders it was 4.1 months. Transfusion independence was achieved in all response groups, particularly those achieving CR.

Serious adverse events were reported in the majority of patients; the most frequent being febrile neutropenia, anaemia, and thrombocytopenia. Treatment-related adverse events of special interest included differentiation syndrome, which was reported in 21 patients (14%).

1. Molenaar RJ, et al. Oncogene 2018;37:1949–1960.
2. De Botton S, et al. Effect of olutasidenib (FT-2102) on complete remissions in patients with relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML): Results from a planned interim analysis of a phase 2 clinical trial. Abstract 7006, ASCO 2021 Virtual Meeting, 4–8 June.

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Posted on 12 August 202117 August 2021