On May 25, 2022, the FDA accelerated the approval of ivosidenib tablets (Tibsovo; Servier Pharmaceuticals) in combination with azacitidine tablets (Onureg; Celgene) for newly diagnosed acute myeloid leukemia (AML) and a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients aged ≥75 years, or patients with comorbidities that preclude the use of intensive induction chemotherapy.
The FDA granted this indication a breakthrough therapy designation. Ivosidenib was previously approved for the treatment of adults with relapsed or refractory AML and for locally advanced or metastatic cholangiocarcinoma. Oral azacitidine was previously approved for adults with AML who achieved first complete remission (CR) or CR with incomplete blood count recovery after intensive induction chemotherapy and who cannot use intensive curative therapy.
This new indication was approved based on a randomized, multicenter, double-blind, placebo-controlled study of 146 patients with newly diagnosed AML and IDH1 mutation who met ≥1 of the following criteria: age ≥75 years, or having comorbidities that preclude intensive induction chemotherapy, baseline ECOG performance status 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, creatinine clearance <45 mL/min, or another comorbidity.
The patients were randomized (1:1) to ivosidenib, 500 mg daily (N = 72) or to matched placebo orally once daily (N = 74), on days 1 to 28, in combination with azacitidine 75 mg/m2 daily on days 1 to 7 or days 1 to 5, 8, and 9 of each 28-day cycle, until disease progression, unacceptable adverse events, or hematopoietic stem-cell transplant.
The efficacy end points included the rates of event-free survival (EFS), overall survival (OS), and the rate and duration of CR.
The rate of EFS was 65% in the ivosidenib plus azacitidine arm versus 84% in the placebo plus azacitidine arm (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.17-0.72; P = .0038). The median OS was 24 months (95% CI, 11.3-34.1) in the ivosidenib plus azacitidine arm and 7.9 months (95% CI, 4.1-11.3) in the placebo plus azacitidine arm (HR, 0.44; 95% CI, 0.27-0.73; P = .0010). By week 24, the CR rate was 47% (95% CI, 35%-59%) versus 15% (95% CI, 8%-25%), respectively. The median duration of CR was not estimable (NE) in the ivosidenib plus azacitidine arm (95% CI, 13.0-NE) and was 11.2 months (95% CI, 3.2-NE) in the placebo plus azacitidine arm.
The most common (≥25%) adverse reactions reported with ivosidenib plus azacitidine or as monotherapy are diarrhea, fatigue, edema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, electrocardiogram prolonged QT, differentiation syndrome (which may be life-threatening), and myalgia.
For patients without disease progression or unacceptable adverse events, treatment with this regimen is recommended for a minimum of 6 months, to allow time for clinical response.