The Food and Drug Administration (FDA) has approved Tibsovo® (ivosidenib) in combination with azacitidine for newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

The approval was based on data from the phase 3 AGILE trial (ClincialTrials.gov Identifier: NCT03173248) that included 146 patients with newly-diagnosed AML with an IDH1 mutation who met at least 1 of the following criteria: age 75 years or older, baseline Eastern Cooperative Oncology Group performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin less than 1.5 times the upper limit of normal, creatinine clearance greater than 45mL/min, or other comorbidity. 

Patients were randomly assigned to receive ivosidenib 500mg or placebo orally once daily on days 1 to 28 in combination with azacitidine 75mg/m2/day either subcutaneously or intravenously on days 1 to 7 (or days 1 to 5 and 8 to 9) of each 28 days cycle beginning on cycle 1 day 1. Study participants received a minimum of 6 cycles of treatment unless they experienced disease progression, unacceptable toxicity or underwent hematopoietic stem cell transplantation.

The primary endpoint of the study was event free survival (EFS), defined as the time from randomization until treatment failure (failure to achieve complete remission by week 24), relapse from remission, or death from any cause, whichever occurred first.

Results showed a statistically significant improvement in EFS (hazard ratio [HR], 0.35; 95% CI 0.17-0.72; P = .0038) and overall survival (OS; secondary endpoint) (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 groups, respectively (HR 0.44; 95% CI, 0.27-0.73; P =.0010).

Complete remission (CR) was 47% (95% CI, 35-59) with ivosidenib plus azacitidine and 15% (95% CI, 8-25) with placebo plus azacitidine. Median duration of CR was not estimable (NE) in the ivosidenib plus azacitidine group (95% CI, 13.0, NE) and 11.2 months (95% CI, 3.2, NE) in the placebo plus azacitidine group. The median time to first CR for ivosidenib with azacitidine was 4 months (range, 1.7-11.9).

The new indication for AML expands on a previously approved monotherapy regimen for patients with newly diagnosed AML with IDH1 mutation. Tibsovo is also approved to treat refractory AML and cholangiocarcinoma.

References

  1. Servier Announces FDA approval of Tibsovo® (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. News release. May 25, 2022. https://www.prnewswire.com/news-releases/servier-announces-fda-approval-of-tibsovo-ivosidenib-tablets-in-combination-with-azacitidine-for-patients-with-newly-diagnosed-idh1-mutated-acute-myeloid-leukemia-301555363.html
  2. Tibsovo. Package insert. Servier; 2022. Accessed May 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211192s009lbl.pdf