Isocitrate dehydrogenase 1 (IDH1) mutations are oncogenic factors in acute myeloid leukemia (AML), with mutant IDH1 (mIDH1) present in 6–10% of AML patients. The carcinogenic pathways that are triggered by this mutation are silenced by the small molecule mIDH1 inhibitor ivosidenib (IVO). For a study, researchers sought to evaluate the effectiveness and safety of IVO with azacitidine (AZA) as a first-line treatment for AML patients who cannot receive intense chemotherapy (IC). The study was a randomized, placebo (PBO)-controlled, international phase 3 trial.

Ineligible for IC were patients with untreated AML who had a centrally verified mIDH1 status. IVO 500 mg (or PBO) once a day + AZA 75 mg/m2 for 7 days in cycles of 28 days. Response rates, blood counts, dependency on transfusions, health-related quality of life (HRQoL), event-free survival (EFS), overall survival (OS), and adverse events (AEs).

IVO+AZA (n = 72) and PBO+AZA (n = 74) were randomly administered to 146 individuals. 76.0 and 75.5 years old, respectively, were the median ages. IVO+AZA had a considerably better EFS (HR=0.33; 1-sided P=0.0011). IVO+AZA and PBO+AZA had a median OS of 24.0 months and 7.9 months, respectively (HR=0.44; 1-sided P=0.0005). IVO+AZA and PBO+AZA had complete response rates of 47.2% and 14.9%, respectively (P<0.0001). Only the IVO+AZA therapy group’s absolute neutrophil count increased after the first 2 weeks of treatment (from 0.99×109/L at baseline to 2.05×109/L at week 2). Patients in the IVO+AZA group developed RBC and platelet transfusion independence significantly more frequently (2-sided P=0.006). From treatment cycles 5 to 19, IVO+AZA retained or enhanced HRQoL, whereas PBO+AZA showed only modestly clinically significant benefits. Anemia (25.4% vs. 26.0%), febrile neutropenia (28.2% vs. 34.2%), thrombocytopenia (23.9% vs. 20.5%), pneumonia (22.5% vs. 28.8%), and infections (21.1% vs. 30.1%) were among the grade more or around 3 adverse events (AEs) that occurred in more than 20% of patients receiving IVO+AZA vs. PBO+AZA.

IVO+AZA significantly improved EFS, OS, and clinical response in patients with newly diagnosed, IC ineligible mIDH1 AML as compared to PBO+AZA. Patients who had IVO+AZA had blood counts that recovered quickly, were less dependent on RBC/platelet transfusions than those who received PBO+AZA, and had better HRQoL. IVO+AZA had a better safety profile than PBO+AZA, with less febrile neutropenia and infection occurrences.

Reference: SOHO