Activity of Ivosidenib in IDH1-Mutated Relapsed or Refractory Acute Myeloid Leukemia
As reported at the 2018 ASCO Annual Meeting and in The New England Journal of Medicine by DiNardo et al, early-phase testing has shown activity of ivosidenib, an oral small-molecule inhibitor of mutant IDH1, in patients with IDH1-mutated relapsed or refractory acute myeloid leukemia (AML). IDH1 mutation is estimated to occur in 6% to 10% of patients with acute AML.
Study Details
In a phase I dose-escalation and dose-expansion study, a total of 258 patients received ivosidenib monotherapy. Among these, 179 received a starting dose of 500 mg/d. The primary efficacy population consisted of patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with ≥ 6 months of follow-up at time of analysis.
Adverse Events
Among the total of 179 patients with relapsed or refractory AML who received a starting dose of ivosidenib of 500 mg/d, treatment-related adverse events of grade ≥ 3 occurred in 20.7%, with the most common being prolongation of QT interval (7.8%), IDH differentiation syndrome (3.9%), anemia (2.2%), thrombocytopenia or decreased platelet count (3.4%), and leukocytosis (1.7%).
Responses
In the primary efficacy population of 125 patients, the rate of complete remission or complete remission with partial hematologic recovery was 30.4%, rate of complete remission was 21.6%, and overall response rate was 41.6%. Respective median durations of response were 8.2, 9.3, and 6.5 months. Transfusion independence was observed in 29 (35%) of 84 initially transfusion-dependent patients. Patients with complete remission or complete remission with partial hematologic recovery had lower risk of infection and febrile neutropenia vs patients without response. No detectable residual IDH1 mutations were found on polymerase chain reaction in 7 (21%) of the 34 patients with complete remission or complete remission with partial hematologic recovery.
The investigators concluded, “In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission.”
The study was funded by Agios Pharmaceuticals.
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