ON JULY 20, 2018, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test.1,2 The FDA simultaneously approved the Abbott RealTime IDH1 assay for use in selecting patients for treatment with ivosidenib.
Supporting Efficacy Data
APPROVAL WAS BASED on the findings of a single-arm multicenter trial, in which 174 patients received oral ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation.2,3 The median treatment duration was 4.1 months. Overall, 21 patients (12%) received a stem cell transplant after ivosidenib treatment. The rate of complete remission plus complete remission with partial hematologic recovery was 32.8% (complete remission in 24.8%, complete remission with partial hematologic recovery in 8.0%). The median time to response was 2 months (range = 0.9–5.6 months). The median response duration was 8.2 months.
Among 110 patients dependent on red blood cell (RBC) or platelet transfusion at baseline, 41 (37.3%) became independent of such transfusions during any 56-day postbaseline period. Of 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion-independent during any 56-day postbaseline period.
How It Works
IVOSIDENIB IS a small-molecule inhibitor of the mutant IDH1 enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in leukemia cells and where efficacy is predicted by (1) clinically meaningful remissions with the recommended dose of ivosidenib and/or (2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex vivo, reduced blast counts, and increased percentages of mature myeloid cells.
How It Is Used
THE RECOMMENDED DOSE of ivosidenib is 500 mg once daily until disease progression or unacceptable toxicity. Patients without disease progression or unacceptable toxicity should be treated for a minimum of 6 months to allow time for clinical response. Ivosidenib should not be taken with a high-fat meal, which results in an increased ivosidenib concentration.
Product labeling provides detailed instructions on dose modification and management for differentiation syndrome; noninfectious leukocytosis; QTc interval > 480 to 500 msec; QTc interval > 500 msec; QTc interval prolongation with signs or symptoms of life-threatening arrhythmia; Guillain-Barré syndrome; and other grade ≥ 3 toxicity considered related to treatment.
THE MOST COMMON adverse events of any grade among the 179 patients receiving ivosidenib in the single-arm trial were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT prolongation, rash, pyrexia, cough, and constipation. The most common serious adverse events were differentiation syndrome, leukocytosis, and QT prolongation. Adverse events that led to permanent discontinuation included Guillain-Barré syndrome, rash, stomatitis, and increased creatinine.
Ivosidenib has a boxed warning for differentiation syndrome. Patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, corticosteroid therapy should be started, and hemodynamic monitoring should be performed until symptom resolution. Ivosidenib also carries warnings/precautions for QTc interval prolongation and Guillain-Barré syndrome. Blood cell counts and blood chemistries should be assessed prior to the initiation of treatment, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Blood creatine phosphokinase should be monitored weekly for the first month of therapy. Electrocardiograms should be monitored at least once weekly for the first 3 weeks and then at least once monthly for the duration of therapy. Patients should not breastfeed while receiving ivosidenib. ■
1. U.S. Food and Drug Administration: FDA approves ivosidenib for relapsed or refractory acute myeloid leukemia. Available at www.fda.gov. Accessed August 6, 2018.
3. DiNardo CD, Stein EM, de Botton S, et al: Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 378:2386-2398, 2018.