The U.S. Food and Drug Administration (FDA) has granted approval to ivosidenib (Tibsovo, Servier) in combination with azacitidine for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) harboring an isocitrate dehydrogenase-1 (IDH1) mutation. This approval marks a significant advancement for patients who are either 75 years or older or have comorbidities that prevent the use of intensive induction chemotherapy.
The approval is based on the results of the phase 3 AGILE trial, a multicenter, double-blind, randomized, placebo-controlled study. The trial compared ivosidenib plus azacitidine to placebo plus azacitidine in patients with previously untreated IDH1-mutated AML. The study's primary endpoint was event-free survival (EFS).
The AGILE trial included 146 patients with a median age of 75.5 years. Results demonstrated that the addition of ivosidenib to azacitidine significantly extended both EFS (HR = 0.35; 95% CI, 0.17-0.72; 2-sided P = 0.0038) and overall survival (OS) (HR = 0.44; 95% CI, 0.27-0.73; 1-sided P = 0.0005). The median OS was 24.0 months in the ivosidenib/azacitidine arm compared to 7.9 months in the placebo/azacitidine arm.
Clinical Response and Safety
The combination of ivosidenib and azacitidine also showed a favorable clinical response. The complete response (CR) rate was 47.2% (95% CI, 35.3%-59.3%) in the ivosidenib/azacitidine arm compared to 14.9% (95% CI, 7.7%-25.0%) in the placebo/azacitidine arm (P < .0001). The rate of complete response plus complete response with partial hematologic recovery (CRh) was 52.8% (95% CI, 40.7%-64.7%) versus 17.6% (95% CI, 9.7%-28.2%), respectively (P < .0001).
The median time to response was 4.3 months in the ivosidenib arm and 3.8 months in the placebo arm. The overall response rate (ORR) was 62.5% (95% CI, 50.3%-73.6%) with ivosidenib plus azacitidine compared to 18.9% (95% CI, 10.7%, 29.7%) with placebo plus azacitidine (P < .0001).
In terms of safety, the most common adverse events (AEs) in the ivosidenib group were nausea (42.3%), vomiting (40.8%), and diarrhea (35.2%). The safety profile of the combination was consistent with previous reports. Grade 3 or higher AEs were reported in 93.0% of patients receiving ivosidenib plus azacitidine and 94.5% of those receiving placebo plus azacitidine.
Expert Commentary
Eytan M. Stein, MD, director of the Program for Drug Development in Leukemia at Memorial Sloan Kettering Cancer Center, noted, "In addition to a favorable safety profile, Tibsovo is the first therapy targeting cancer metabolism to demonstrate an impressive, significant benefit in event-free survival and overall survival in combination with azacitidine, underscoring its importance as part of a new combination regimen for patients with newly diagnosed IDH1-mutated acute myeloid leukemia who are not candidates for intensive induction chemotherapy."
