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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Friday, July 20, 2018

Ivosidenib FDA-Approved for Adult Patients With R/R Acute Myeloid Leukemia & an IDH1 Mutation

Ivosidenib has been granted approval from the FDA for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test. Ivosidenib, an oral, targeted inhibitor of the IDH1 enzyme, is the first and only FDA-approved therapy for patients with R/R AML and an IDH1 mutation.

Given that the majority of patients with AML eventually relapse, R/R AML has a poor prognosis. The 5-year survival rate is approximately 27 percent (Genes Cancer 2011;2:95-107). For 6-10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia.

"AML patients who relapse or are refractory to available therapies have few, if any, treatment options," said Hagop M. Kantarjian, MD, Professor and Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston. "The clinical study demonstrated that [ivosidenib] has the potential to deliver strong, durable responses as a single agent and can help patients achieve and maintain transfusion independence. IDH inhibitors represent a new class of noncytotoxic, targeted therapies for AML patients with IDH mutations."

Safety & Efficacy Data

The FDA approval was based on the clinical data from an open-label, single-arm, multicenter dose-escalation and expansion trial of adult patients with R/R AML and an IDH1 mutation (Study AG120-C-001, NCT02074839). Ivosidenib was approved concurrently with the Abbott RealTime IDH1 companion diagnostic test for selection of patients with R/R AML for treatment with ivosidenib.  

The efficacy of ivosidenib was evaluated in 174 adult patients with R/R AML with an IDH1 mutation identified or confirmed by the Abbott RealTime IDH1 assay. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Patients had a median age of 67 years (range of 18-87) and received a median of two prior anticancer therapies (ranging from 1-6). More than half (63%) were refractory to previous therapy and 33% had secondary AML. The primary endpoint is the combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate. CRh is defined as <5 percent of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

In this trial, ivosidenib demonstrated:

  • CR+CRh rate of 32.8 percent (57 of 174 patients) (95% CI: 25.8, 40.3). 
  • The CR rate was 24.7 percent (43 of 174 patients) (95% CI 18.5, 31.8) and the CRh rate was 8 percent (14 of 174 patients) (95% CI 4.5, 13.1). 
  • Median duration of CR+CRh was 8.2 months (95% CI: range 5.6, 12 months). 
  • For patients who achieved a CR or CRh, the median time to best response of CR or CRh was 2.0 months (range, 0.9-5.6 months). 
  • Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. 
  • Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.
  • Twenty-one of the 174 patients (12%) went on to stem cell transplant following ivosidenib treatment. 

The safety profile of single-agent ivosidenib was evaluated in 179 patients with R/R AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range 0.1 to 39.5 months). In the clinical trial, 19 percent (34/179) of patients treated with ivosidenib experienced differentiation syndrome, which can be fatal if not treated. QTc interval prolongation and Guillain-Barré Syndrome occurred in patients treated with ivosidenib. 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%). ​