On October 24, 2023, the FDA approved ivosidenib (Tibsovo; Servier Pharmaceuticals), an oral tyrosine kinase inhibitor, for the treatment of relapsed or refractory myelodysplastic syndromes (MDS) in adults with a susceptible IDH1 mutation, as detected by an FDA-approved test. Ivosidenib was granted priority review and received breakthrough therapy and orphan drug designations for this indication.
The Abbott RealTime IDH1 Assay was also approved by the FDA as a companion diagnostic device to select patients who qualify for treatment with ivosidenib.
“Today’s approval represents an important treatment advancement for rare blood cancers, and more specifically, patients with relapsed or refractory MDS who have an IDH1 mutation. Through the FDA’s Oncology Center of Excellence Rare Cancers Program, we remain committed to promoting scientific innovation and advancing the development of safe and effective novel therapies to treat patients with rare cancers,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence, and Acting Director, Office of Oncologic Diseases, FDA’s Center for Drug Evaluation and Research, in a press release.
The approval of ivosidenib for MDS was based on results of AG120-C-001, an open-label, single-arm, multicenter clinical trial of 18 adults with relapsed or refractory MDS and IDH1 mutation as detected in peripheral blood or bone marrow by a local or central diagnostic test. The presence of these mutations was confirmed retrospectively by the Abbott RealTime IDH1 Assay.
In the AG120-C-001 trial, patients received 500 mg daily of oral ivosidenib until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median duration of treatment with ivosidenib was 9.3 months. One patient underwent a stem cell transplantation after receiving ivosidenib.
The primary efficacy end point of AG120-C-001 was the rate of complete remission (CR) or partial remission (PR) as defined by 2006 International Working Group response for MDS, CR plus PR durations, and the conversion rate from transfusion dependence to independence. The response rate was 39% (95% confidence interval, 17%-64%), and all responses observed were CRs. The median time to CR was 1.9 months (range, 1.0-5.6 months), and the median CR duration was not estimable (range, 1.9-80.8+ months). Among the 9 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 6 (67%) became RBC and platelet transfusion independent during any 56-day postbaseline period. Among the 9 patients who did not require RBC and platelet transfusions at baseline, 7 (78%) remained transfusion independent during any 56-day post-baseline period.
The most common (≥20%) adverse reactions observed with ivosidenib were similar to those observed with ivosidenib monotherapy in patients with acute myeloid leukemia, for which ivosidenib is also FDA approved. These adverse reactions include diarrhea, constipation, mucositis, nausea, arthralgia, fatigue, cough, myalgia, and rash. Ivosidenib has a Boxed Warning about the risk for differentiation syndrome, which can be fatal. Ivosidenib can also cause QTc interval prolongation.
The recommended dose of ivosidenib is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. Patients should be counseled to avoid taking ivosidenib with a high-fat meal.
