On May 25, 2022, ivosidenib was approved for use in combination with azacitidine for newly diagnosed acute myeloid leukemia with a susceptible IDH1 mutation, as detected by a U.S. Food and Drug Administration–approved test, in patients aged 75 or older or in those who have comorbidities precluding the use of intensive induction chemotherapy.1
Supporting Efficacy Data
Approval was based on the findings in the multicenter, double-blind AG120-C-009 trial (ClinicalTrials.gov identifier NCT03173248). A total of 146 patients were randomly assigned to receive ivosidenib at 500 mg daily (n = 72) or placebo (n = 74) continuously in combination with azacitidine at 75 mg/m2 daily on days 1 to 7 or days 1 to 5 and 8 to 9 of 28-day cycles until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. Patients had to be aged 75 or older or have an Eastern Cooperative Oncology Group performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin more than 1.5 times the upper limit of normal, creatinine clearance less than 45 mL/min, or other comorbidities.
Event-free survival events occurred in 65% of the ivosidenib group vs 84% of the control group (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) vs 7.9 months (95% CI = 4.1–11.3 months; HR = 0.44, 95% CI = 0.27–0.73, P = .0010). Complete remission rate was 47% vs 15% (P < .0001), with a median remission duration of not estimable vs 11.2 months.
How It Is Used
The recommended dose of ivosidenib is 500 mg once daily starting 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.
In the AG120-C-009 trial, the most common adverse events of any grade in the ivosidenib group were nausea (42% vs 38% in the control group), vomiting (41% vs 27%), arthralgia (30% vs 8%), dyspnea (20% vs 15%), and QT prolongation (20% vs 7%). The most common grade 3 or 4 adverse events were QT prolongation and differentiation syndrome (10% each). The most common grade 3 or 4 laboratory abnormalities were decreases in leukocytes (55%), hemoglobin (46%), platelets (42%), and neutrophils (23%).
Ivosidenib has a boxed warning for differentiation syndrome and warnings/precautions for QTc interval prolongation and Guillain-Barré syndrome.
The most common serious adverse event was differentiation syndrome (8%). Adverse events leading to discontinuation of treatment in at least 2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%). Fatal adverse events occurred in 4% of patients, because of differentiation syndrome in 3% and cerebral ischemia in one patient.
Ivosidenib has a boxed warning for differentiation syndrome. It has warnings/precautions for QTc interval prolongation and Guillain-Barré syndrome. Patients should be advised not to breastfeed while taking ivosidenib.
1. Tibsovo (ivosidenib tablets), for oral use, prescribing information, Servier Pharmaceuticals LLC, May 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211192s009lbl.pdf. Accessed June 6, 2022.