FDA Approves Ivosidenib/Azacitidine for Certain Patients With Newly Diagnosed AML

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On May 25, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo) in combination with azacitidine for patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in adults aged 75 or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.


Approval was based on a randomized, multicenter, double-blind, placebo-controlled study (AG120-C-009, identifier: NCT03173248) that included 146 patients with newly diagnosed AML with an IDH1 mutation who met at least one of the following criteria:

  • Age 75 years or older
  • Baseline Eastern Cooperative Oncology Group performance status of 2
  • Severe cardiac or pulmonary disease
  • Hepatic impairment with bilirubin > 1.5 times the upper limit of normal
  • Creatinine clearance < 45 mL/min
  • Other comorbidity.

Patients were randomly assigned 1:1 to receive ivosidenib at 500 mg daily (n = 72) or matched placebo orally once daily (n = 74) on days 1 to 28 in combination with azacitidine at 75 mg/m2/day on days 1 to 7 or days 1 to 5 and 8 and 9 of each 28-day cycle until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation.

Efficacy was established based on improvements in event-free-survival, overall survival, and rate and duration of complete remission. Event-free survival was defined as the time from random assignment until treatment failure, relapse from remission, or death from any cause, whichever occurred first. Treatment failure was defined as failure to achieve complete remission by 24 weeks.

Study Results

Event-free survival events occurred in 65% of patients in the ivosidenib plus azacitidine arm and 84% in the placebo plus azacitidine arm (hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.17–0.72, P = .0038). Median overall survival was 24.0 months (95% CI = 11.3–34.1 months) in the ivosidenib plus azacitidine arm and 7.9 months (95% CI = 4.1–11.3 months) in the placebo plus azacitidine arm (HR = 0.44, 95% CI = 0.27–0.73, P = .0010). Complete remission was 47% (95% CI = 35%–59%) in the ivosidenib plus azacitidine arm and 15% (95% CI = 8%–25%) in the placebo plus azacitidine arm. Median duration of complete remission was not estimable in the ivosidenib plus azacitidine arm (95% CI = 13.0 months–not estimable) and 11.2 months (95% CI = 3.2 months–not estimable) in the placebo plus azacitidine arm.

Adverse Events

The most common adverse reactions to ivosidenib in combination with azacitidine or as monotherapy (≥ 25% in any trial) were diarrhea, fatigue, edema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, and myalgia. Prescribing information contains a Boxed Warning alerting health-care professionals and patients about the risk of differentiation syndrome, which may be life-threatening or fatal.

The recommended ivosidenib dose is 500 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. Start ivosidenib administration on cycle 1, day 1 in combination with azacitidine at 75 mg/m2 subcutaneously or intravenously once daily on days 1 to 7 (or days 1–5 and 8–9) of each 28-day cycle. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response.

This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application about 6 weeks ahead of the FDA goal date.

This application was granted Priority Review and Breakthrough Therapy designation; ivosidenib also received orphan drug designation for AML on June 9, 2015.