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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.

Thursday, May 2, 2019

FDA Approves Supplemental New Drug Application for Ivosidenib as AML Treatment

The FDA has approved a supplemental New Drug Application (sNDA) to update the U.S. Prescribing Information for ivosidenib, an IDH1 inhibitor, to include adult patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

The sNDA was granted Priority Review and accepted under the FDA's Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before the information is formally submitted to the agency. Ivosidenib received initial FDA approval in July 2018 for adult patients with relapsed or refractory (R/R) AML and an IDH1 mutation.

AML is the most common acute leukemia affecting adults with approximately 20,000 new cases estimated in the U.S. each year. AML patients are typically older or have comorbidities that preclude the use of intensive chemotherapy. These patients typically have a worse prognosis and poor outcomes. The majority of patients with AML eventually relapse. The 5-year survival rate is approximately 28 percent. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia. IDH1 mutations have been associated with negative prognosis in AML.

"The phase I results for ivosidenib demonstrated that this oral, single agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation," said Gail J. Roboz, MD, Professor of Medicine, Director of the Leukemia Program and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. "Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics and prior treatment with hypomethylating agents."

The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation who were assigned to receive a 500 mg daily dose. The cohort included patients who were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy (baseline ECOG performance status of ≥2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min). Patients had a median age of 77 years (range of 64 to 87) and 68 percent had AML with myelodysplasia-related changes. 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 42.9 percent (12 of 28 patients) (95% CI: 24.5, 62.8).
  • The CR rate was 28.6 percent (8 of 28 patients) (95% CI 13.2, 48.7) and the CRh rate was 14.3 percent (4 of 28 patients) (95% CI 4.0, 32.7).
  • Median durations of CR and CR+CRh were not estimable, with 5 patients (41.7%) who achieved CR or CRh remaining on ivosidenib treatment (treatment duration range: 20.3 to 40.9 months) as of the data cutoff.
  • 58.3 percent (7 of 12) of patients who achieved CR or CRh were in remission at 1 year after receiving treatment.
  • For patients who achieved a CR or CRh, the median time to best response of CR or CRh was 2.8 months (range, 1.9 to 12.9 months).
  • Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period.
  • Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period.
The safety profile of single-agent ivosidenib was evaluated in 28 patients with newly diagnosed AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 4.3 months (range, 0.3 to 40.9 months). In the clinical trial, 25 percent (7 of 28) of patients treated with ivosidenib experienced differentiation syndrome, which can be fatal if not treated. 

Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. QTc interval prolongation occurred in patients treated with ivosidenib. The most common adverse reactions (≥20%) of any grade in patients with newly diagnosed AML were diarrhea, fatigue, decreased appetite, edema, nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, constipation, differentiation syndrome, dizziness, electrocardiogram QT prolonged, mucositis, and vomiting.