AML-295 AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 Mutation

Context: Isocitrate dehydrogenase 1 (IDH1) mutations are oncogenic drivers in acute myeloid leukemia (AML), with 6–10% of AML patients harboring mutant IDH1 (mIDH1). Ivosidenib (IVO) is a small molecule mIDH1 inhibitor that silences the oncogenic pathways activated by this mutation. Objective: Assess efficacy/safety of IVO+azacitidine (AZA) as frontline therapy for AML patients ineligible for intensive chemotherapy (IC). Design: Randomized, placebo (PBO)-controlled, global phase 3 study. Patients: Patients with untreated AML, centrally confirmed mIDH1 status, ineligible for IC. Interventions: Once daily IVO 500 mg (or PBO) plus AZA 75 mg/m² for 7 days in 28-day cycles. Main Outcome Measures: Event-free survival (EFS), overall survival (OS), response rates, blood counts, transfusion dependence, health-related quality of life (HRQoL), and adverse events (AEs). Results: 146 patients were randomized to IVO+AZA (n=72) and PBO+AZA (n=74). Median age was 76.0 and 75.5 years, respectively. EFS was significantly in favor of IVO+AZA (HR=0.33; 1-sided P=0.0011). Median OS was 24.0 vs 7.9 months for IVO+AZA vs PBO+AZA, respectively (HR=0.44; 1-sided P=0.0005). Complete response rates were 47.2% and 14.9% for IVO+AZA vs PBO+AZA, respectively (P<0.0001). During 2 weeks after treatment initiation, only the IVO+AZA treatment group showed an increase in absolute neutrophil count (from 0.99×10⁹/L at baseline to 2.05×10⁹/L at week 2). Significantly more patients in the IVO+AZA group became RBC and platelet transfusion independent (2-sided P=0.006). IVO+AZA preserved or improved HRQoL from treatment cycles 5 to 19, with few clinically meaningful improvements with PBO+AZA. Grade ≥3 AEs occurring in >20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), pneumonia (22.5% vs 28.8%), and infections (21.1% vs 30.1%). Conclusions: In patients with IC-ineligible, newly diagnosed mIDH1 AML, IVO+AZA significantly improved EFS, OS, and clinical response compared with PBO+AZA. Blood counts rapidly recovered in patients given IVO+AZA, patients were less dependent on RBC/platelet transfusion than those given PBO+AZA, with HRQoL improvements in the IVO+AZA group. The safety profile of IVO+AZA was favorable, with fewer febrile neutropenia and infection events with IVO+AZA vs PBO+AZA.