The Lynx Group

Tibsovo Receives a New Indication, in Combination with Onureg, for Newly Diagnosed Patients with AML and IDH1 Mutation

June 2022, Vol 13, No 3

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 adults with 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 following intensive induction chemotherapy and who are not able to complete intensive curative therapy.

This new indication was approved based on a randomized, multicenter, double-blind, placebo-controlled clinical trial 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 Eastern Cooperative Oncology Group 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 in a 1:1 ratio to oral ivosidenib once daily (N = 72) or to matched oral placebo once daily (N = 74), on days 1 to 28, in combination with oral azacitidine once 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 transplantation.

The primary end point of the trial was event-free survival (EFS), defined as time from randomization until treatment failure (failure to achieve CR by week 24), relapse from remission, or death from any cause, whichever occurred first. Key secondary end points included overall survival (OS) and the rate and duration of CR.

Results showed a statistically significant improvement in EFS (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.17-0.72; P = .0038) and OS (HR, 0.44; 95% CI, 0.27-0.73; P = .0010) with ivosidenib plus azacitidine compared with placebo plus azacitidine. EFS events occurred in 65% of patients in the ivosidenib arm and 84% of patients in the placebo arm.

Median OS was 24.0 months (95% CI, 11.3-34.1) and 7.9 months (95% CI, 4.1-11.3) in the ivosidenib plus azacitidine and placebo plus azacitidine arms, respectively (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 were 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.

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