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FDA Grants Breakthrough Designation to Ivosidenib Combo for Newly Diagnosed IDH1+ AML

Gina Columbus @ginacolumbusonc
Published: Wednesday, Mar 27, 2019

Dr. Chris Bowden
Chris Bowden, MD
The FDA has granted a breakthrough therapy designation to the combination of ivosidenib (Tibsovo) and azacitidine for the treatment of newly diagnosed patients with IDH1-mutant acute myeloid leukemia (AML) ≥75 years old or are ineligible for intensive induction chemotherapy.

The designation is based on data from a phase I/II trial, in which the combination of ivosidenib plus azacitidine led to a 78% overall response rate (ORR), including a 57% complete response (CR) rate in this patient population. The median duration of CR had not been reached (95% CI, 7.7—not estimated), and the 1-year overall survival rate was 82%.

"Outcomes for newly diagnosed AML patients ineligible for intensive chemotherapy are still poor, and there are no approved options specifically for patients with an IDH1 mutation," said Chris Bowden, MD, chief medical officer at Agios Pharmaceuticals. "The Breakthrough Therapy designation provides further support that combining azacitidine and ivosidenib for these patients has the potential to be a compelling treatment option."

In the ongoing phase I/II study, the combination of ivosidenib or enasidenib (Idhifa) plus azacitidine was evaluated in patients with newly diagnosed IDH1-mutant AML who were unable to receive intensive chemotherapy. In the phase Ib portion of the trial, investigators administered 500 mg of ivosidenib daily plus azacitidine in 23 patients.

The median age was 76 years old, and 52% of patients were ≥75 years old. Seventy-four percent of patients had de novo AML and 26% had secondary AML. Moreover, the median number of treatment cycles was 8 (range, 1-22).

As of the August 1, 2018, data cutoff, the mean neutrophil and platelet counts were maintained near or above thresholds for CR with partial hematologic recovery (CRh) while on study treatment with ivosidenib/azacitidine. Fourteen patients remained on study as of the data cutoff.

Moreover, at a median 9.5-month follow-up, results of the ivosidenib arm, which were presented at the 17th International Symposium on Acute Leukemias, showed that 65% of patients had a CR plus CRh, and the median time to response was 1.8 months (range, 0.7-3.8); the median time to CR was 3.5 months (range, 0.8-6).

For patients who achieved a CR, IDH1 mutation clearance was observed in 9 of 13 patients with available bone marrow mononuclear cells and in 10 out of 13 patients with available peripheral blood mononuclear cells, as quantified by a sensitive digital PCR assay with lower limit of sensitivity for mutant IDH1 of 10-4.

Additionally, the safety profile of the combination was consistent with the safety profile of ivosidenib and azacitidine alone in this patient population. The most common all-grade adverse events (AEs) occurring in ≥50% of patients were nausea (61%), diarrhea (57%), anemia (52%), and thrombocytopenia (52%).

The most common grade 3/4 AEs were thrombocytopenia (48%), anemia (44%), and febrile neutropenia (44%). IDH differentiation syndrome was reported in 4 patients, 3 of which were serious AEs. All 4 cases did resolve, including 2 patients who achieved a CR, 1 who had stable disease, and 1 patient was not evaluable for response.

The ongoing, international, multicenter, double-blind, phase III AGILE trial (NCT03173248) is evaluating ivosidenib compared with placebo, both in combination with azacitidine in patients with previously untreated IDH1-mutant AML.

In February 2019, the FDA granted a priority review designation to single-agent ivosidenib for the frontline treatment of patients IDH1-mutant AML who are ineligible for standard chemotherapy. The agency is expected to make a decision on the approval on or before June 21, 2019.

The FDA approved ivosidenib monotherapy for the treatment of adult patients with relapsed/refractory AML with IDH1 mutations in July 2018.


  1. Agios Receives FDA Breakthrough Therapy Designation for TIBSOVO® (ivosidenib) in Combination with Azacitidine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) with an IDH1 Mutation in Adult Patients Ineligible for Intensive Chemotherapy. Agios Pharmaceuticals. Published March 27, 2019. Accessed March 27, 2019.
  2. Agios Reports Updated Data from Phase 1 Study of Ivosidenib in Combination with Azacitidine Demonstrating Deep and Durable Responses in Newly Diagnosed IDH1 Mutant Acute Myeloid Leukemia (AML) Patients. Agios Pharmaceuticals. Published February 25, 2019. Accessed February 25, 2019.

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