On May 25, 2022, 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 variant as detected by an FDA-approved test in adults aged 75 years or older or those who have comorbidities that preclude use of intensive induction chemotherapy.
Approval was based on a randomized, multicenter, double-blind, placebo-controlled study (AG120-C-009; NCT03173248) of 146 patients with newly diagnosed AML with an IDH1 variant who met at least one of the following criteria: aged 75 years or older, baseline 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 per minute, or other comorbidity. Patients were randomized 1:1 to receive ivosidenib 500 mg daily (n = 72) or matched placebo orally once daily (n = 74) on days 1–28 in combination with azacitidine 75 mg/m2 per day on days 1–7 or days 1–5 and 8–9 of each 28-day cycle until they experienced disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation.
Efficacy was established based on improvements in event-free-survival (EFS), overall survival (OS), and rate and duration of complete remission (CR). EFS was defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurred first. Treatment failure was defined as failure to achieve CR by 24 weeks. EFS events occurred in 65% of patients on the ivosidenib plus azacitidine arm and 84% on the placebo plus azacitidine arm (HR = 0.35; 95% CI = 0.17, 0.72, p = 0.0038). 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 = 0.0010). CR 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 CR was not estimable (NE) in the ivosidenib plus azacitidine arm (95% CI = 13.0, NE) and 11.2 months (95% CI = 3.2, NE) in the placebo plus azacitidine arm.
The most common adverse reactions reported in 25% or more of patients in any trial were diarrhea, fatigue, edema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, prolonged electrocardiogram QT, differentiation syndrome, and myalgia. Prescribing information contains a boxed warning alerting healthcare 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 patients experience disease progression or unacceptable toxicity. Start ivosidenib administration on cycle 1, day 1, in combination with azacitidine 75 mg/m2 subcutaneously or via IV infusion once daily on days 1–7 or days 1–5 and 8–9 of each 28-day cycle. Treatment is recommended for a minimum of six months to allow time for clinical response for patients without disease progression or unacceptable toxicity.
View the full prescribing information for ivosidenib.
The 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 FDA’s assessment. FDA approved the application about six weeks ahead of FDA’s goal date.
The application was granted priority review and breakthrough designation. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics. Ivosidenib also received orphan drug designation for AML on June 9, 2015.
Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.
For assistance with single-patient investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.