AZA/VEN + ivosidenib (IDH1 inhibitor) drives 95% ORR and 79% 3-year OS in unfit IDH1-mut AML

Azacitidine (DNA hypomethylating agent) + venetoclax (BCL-2 inhibitor) + ivosidenib (mutant IDH1 inhibitor) was evaluated as a frontline “triplet” in a multicenter Phase Ib/II study (NCT03471260) for newly diagnosed IDH1-mutated AML in adults ineligible for intensive induction (n=40; median age 72). ORR was 95% with 93% composite CR (CR/CRh/CRi) and 92% MRD-negativity among CRc responders; at median follow-up 35 months, median OS and DOR were not reached and 3-year OS was 79%—numerically above the approved AZA+IVO benchmark (AGILE: median OS 24.0 months vs 7.9 months with AZA alone; HR 0.44) and above typical frontline AZA+VEN outcomes in unfit AML (VIALE-A: median OS 14.7 months vs 9.6 months with AZA alone), acknowledging this is cross-trial and IDH1-selected. Grade ≥3 non-hematologic AEs occurred in 30% (mostly infections 23%); grade ≥3 QTc prolongation, tumor lysis syndrome, and differentiation syndrome each occurred in 5% (2/40) and were managed with supportive care/dose modification; 45% proceeded to transplant, and only 2 patients discontinued for AEs.