FDA OKs Targeted Agent Ivosidenib for Relapsed/Refractory AML

Roxanne Nelson, BSN, RN


July 20, 2018

The US Food and Drug Administration (FDA) has approved the targeted agent ivosidenib (Tibsovo, Agios Pharmaceuticals) for adults with relapsed or refractory acute myeloid leukemia (AML) who harbor isocitrate dehydrogenase-1 (IDH1) mutations. 

At the same time, the FDA has also approved the RealTime IDH1 Assay (Abbott Laboratories), a companion diagnostic used to detect specific mutations in the IDH1 gene in blood or bone marrow samples from patients with AML. 

"Tibsovo is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH1 mutation," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

Padzur added in a statement from the agency that the use of Tibsovo is "associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions."

Mutations in the gene encoding IDH1 occur in approximately 6% to 10% of patients with AML. Ivosidenib, a first-in-class agent, is an oral, targeted, small-molecule inhibitor of mutant IDH1.

Last year the FDA approved enasidenib (Idhifa, Celgene),  an oral targeted inhibitor of the IDH2 enzyme for treatment of relapsed or refractory AML with an IDH2 mutation. Similarly, it was also approved for use with a companion diagnostic, the RealTime IDH2 Assay (Abbott Laboratories).

The new approval was based on results of a single-arm trial that included 174 adult patients with relapsed or refractory AML and an IDH1 mutation. Patients had a median age of 67 years (range, 18 to 87 years) and had received a median of two prior anticancer therapies (ranging from one to six). More than half (63%) were refractory to previous therapy and 33% had secondary AML.

At a median follow-up of 8.3 months, 32.8% (n = 57) of patients experienced complete remission (CR) or CR with partial hematologic recovery (CRh) that lasted for a median of 8.2 months. The CR rate was 24.7% (43 of 174 patients; 95% confidence interval [CI], 18.5% - 31.8%) and the CRh rate was 8% (14 of 174 patients; 95% CI, 4.5% - 13.1%).

Among 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) achieved transfusion independence during any 56-day postbaseline period.

Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during the same period.

In addition, 21 patients were able to become eligible for stem cell transplant following treatment.

The safety profile was evaluated in 179 patients who were treated with a dose of 500 mg daily, and the median duration of exposure was 3.9 months (range, 0.1 to 39.5 months). Of this group, 19% (34/179)  experienced potentially fatal differentiation syndrome; prolonged corrected QT interval and Guillain-Barré syndrome also occurred.

The most common adverse reactions (≥20%) of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation. The most frequent serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%) and electrocardiogram QT prolonged (7%).

Ivosidenib was granted Fast Track and Priority Review designations and also received Orphan Drug designation.

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