On October 24, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo) for adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test.
The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for treatment with ivosidenib.
AG120-C-001
Approval was based on trial AG120-C-001 (ClinicalTrials.gov identifier NCT02074839), an open-label, single-arm, multicenter trial of 18 adult patients with relapsed or refractory MDS with an IDH1 mutation; mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 Assay.
Ivosidenib was administered orally at a starting dose of 500 mg daily continuously for 28-day cycles until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 9.3 months. One patient underwent a stem cell transplantation following ivosidenib.
Efficacy was established by the rate of complete or partial remission (2006 International Working Group response for MDS), complete and partial remission durations, and conversion rate from transfusion dependence to independence.
All observed responses were complete remissions. The complete remission rate was 38.9% (95% confidence interval [CI] = 17.3%–64.3%). The median time to complete remission was 1.9 months (range = 1.0–5.6 months), and the median complete remission duration was not estimable (range = 1.9–80.8+ months). Among nine patients dependent on red blood cell and/or platelet transfusions at baseline, six (67%) became red blood cell and platelet transfusion–independent during any 56-day postbaseline period. Of the nine patients independent of both red blood cell and platelet transfusions at baseline, seven (78%) remained transfusion-independent during any 56-day postbaseline period.
The most common adverse reactions were similar to those observed with ivosidenib monotherapy for acute myeloid leukemia. These included gastrointestinal toxicities (diarrhea, constipation, mucositis, and nausea), arthralgia, fatigue, cough, myalgia, and rash. Ivosidenib may also cause QTc prolongation.
The prescribing information contains a Boxed Warning alerting health-care professionals and patients about the risk of differentiation syndrome, which may be life-threatening or fatal.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review, Breakthrough designation, and Orphan Drug designation.
