June 2022: Ivosidenib (Tibsovo, Servier Pharmaceuticals LLC) in combination with azacitidine has been approved by the Food and Drug Administration for newly diagnosed acute myeloid leukaemia (AML) in adults 75 years or older with a susceptible IDH1 mutation, as detected by an FDA-approved test, or who have comorbidities that prevent intensive induction chemotherapy.
The FDA granted approval based on the results of a randomised, multicenter, double-blind, placebo-controlled study (AG120-C-009, NCT03173248) that enrolled 146 patients with newly diagnosed AML with an IDH1 mutation who satisfied at least one of the following criteria: age 75 years or older, ECG performance status 2, significant cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, creatinine clearance 45 mL/min, or other comorbidities On Days 1-28, patients were randomised 1:1 to receive ivosidenib 500 mg daily (N=72) or a matched placebo orally once daily (N=74) in combination with azacitidine 75 mg/m2/day on Days 1-7 or Days 1-5 and 8-9 of each 28-day cycle until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation
Improvements in event-free survival (EFS), overall survival (OS), and the rate and duration of full remission were used to determine efficacy (CR). The period from randomization to treatment failure, relapse from remission, or death from any cause, whichever came first, was called EFS. Failure to attain CR within 24 weeks was considered as treatment failure. EFS occurred in 65 percent of ivosidenib plus azacitidine patients and 84 percent of placebo plus azacitidine patients (HR 0.35; 95 percent CI: 0.17, 0.72, p=0.0038). The median OS in the ivosidenib plus azacitidine arm was 24.0 months (95 percent CI: 11.3, 34.1), while the placebo plus azacitidine arm was 7.9 months (95 percent CI: 4.1, 11.3) (HR 0.44; 95 percent CI: 0.27, 0.73; p=0.0010). The CR rate in the ivosidenib plus azacitidine arm was 47 percent (95 percent CI: 35 percent, 59 percent) and 15 percent (95 percent CI: 8 percent, 25 percent) in the placebo plus azacitidine arm. The median duration of CR in the ivosidenib plus azacitidine arm was not estimable (NE) (95 percent confidence interval: 13.0, NE) and 11.2 months (95 percent confidence interval: 3.2, NE) in the placebo plus azacitidine arm.
Diarrhea, fatigue, edoema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, and myalgia were the most common adverse reactions of ivosidenib in combination with azacitidine or as monotherapy (25 percent in any trial). A Boxed Warning on the prescribing instructions warns health care professionals and patients about the possibility of differentiation syndrome, which can be deadly or life-threatening.
Ivosidenib is prescribed at a dose of 500 mg once daily, with or without food, until disease progression or unacceptable toxicity. On Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle, begin administering ivosidenib in conjunction with azacitidine 75 mg/m2 subcutaneously or intravenously once daily. Treatment is suggested for a minimum of 6 months for patients without illness progression or significant toxicity to give time for clinical response.
