FDA Grants Ivosidenib Priority Review for Frontline IDH1+ AML

The FDA has granted a priority review to a supplemental new drug application for ivosidenib for the frontline treatment of patients IDH1-mutant acute myeloid leukemia who are ineligible for standard chemotherapy.

Chris Bowden, MD

The FDA has granted a priority review to a supplemental new drug application (sNDA) for ivosidenib (Tibsovo) for the frontline treatment of patients IDH1-mutant acute myeloid leukemia (AML) who are ineligible for standard chemotherapy.

The sNDA is based on data from a phase I trial in which ivosidenib induced an overall response rate (ORR) of 57.6% (95% CI, 39.2-74.5) among newly diagnosed patients with IDH1-positive AML.1 The ORR included a 42.4% (95% CI, 25.5-60.8) combined rate of complete remission (CR) plus CR with partial hematologic recovery (CRh).

Under the expedited priority review, the FDA will review the sNDA within 6 months from the acceptance of the filing, compared with the standard 10 months. An approval decision is scheduled to be made on or before June 21, 2019.

“In less than 7 months since Tibsovo's approval in relapsed or refractory AML, we are pleased to be working with the FDA to expand its labeled indication into the frontline setting,” Chris Bowden, MD, chief medical officer of Agios, the manufacturer of ivosidenib, said in a press release.

“Patients with newly diagnosed AML who are not eligible for standard treatments, such as intensive and nonintensive chemotherapy, are currently offered only palliative care. There is tremendous need for new treatment options, and we believe AML patients with IDH1 mutations have the potential to benefit from this targeted therapy,” added Bowden.

Agios submitted data from a phase I dose escalation/expansion study examining ivosidenib monotherapy in patients with IDH1-positive hematologic malignancies. Study results from the data cutoff date of May 11, 2018, were presented in December 2018 at the ASH Annual Meeting. At the cutoff, 258 patients had received treatment, including 34 patients with untreated AML. Of this group, 9 were from the dose-escalation phase and 25 were from the expansion phase.

Among these 34 AML patients, 79.4% had secondary AML and 20.6% had de novo AML. The median patient age was 76.5 years (range, 64-87). Patients received 500 mg of ivosidenib daily, and the median treatment duration was 4.3 months (range, 0.3-35.1).

Efficacy data were available for 33 of the AML patients. The CR rate was 30.3% (10 of 33 patients) and the CRh rate was 12.1% (4 of 33 patients). Among all responders, the median time to first response was 1.9 months (range, 0.9-3.6). The median time to CR/CRh was 2.8 months (range, 1.9-12.9). The estimated 12-month durations of response were 59.5%, 66.7%, and 77.8%, in the ORR, CR/CRh, and CR populations, respectively.

There were patients across all categories of responders who achieved transfusion independence (no transfusions for ≥56 consecutive days on treatment). Sixty-four percent (9 of 14) of the CR/CRh group had IDH1 mutation clearance, including all 4 patients who achieved a CRh.

The safety population included all 34 patients with untreated AML. Adverse events (AEs) across all grades occurring in >25% of patients were diarrhea (52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), and edema peripheral (26.5%).

Of note, 8.8% of patients had grade ≥3 ECG QT prolongation. ECG QT prolongation of any grade led to ivosidenib doses being reduced in 2 patients and held in 4 patients. Three percent of patients had grade ≥3 leukocytosis. IDH-differentiation syndrome (IDH-DS) across all grades occurred in 17.6% of patients. The IDH-DS, which was managed with corticosteroids and diuretics, led to 3 patients having their dose temporarily held but no dose reductions.

The FDA approved ivosidenib in July 2018 for the treatment of adult patients with relapsed/refractory IDH1-mutant AML.2 The approval was based on a single-arm phase I study of 174 patients with IDH1-positive relapsed/refractory AML. In the study, the CR rate was 24.7% (95% CI, 18.5-31.8) and the CRh rate was 8% (95% CI, 4.5-13.1). The median duration of CR plus CRh was 8.2 months (range, 5.6-12). Among the CR/CRh population, the median time to best response was 2.0 months (range, 0.9-5.6).


  1. Agios Presents Updated Data from the Ivosidenib Phase 1 Dose-Escalation and Expansion Trial in IDH1 Mutant Positive Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Ineligible for Standard Treatment and Myelodysplastic Syndrome (MDS). Agios. Published December 3, 2018. Accessed February 20, 2019. https://bit.ly/2Gydl0p.
  2. FDA Grants Approval of TIBSOVO®, the First Oral, Targeted Therapy for Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia and an IDH1 Mutation. Agios. Published July 20, 2018. Accessed February 20, 2019. https://bit.ly/2mwqScv.