Gilteritinib plus azacitidine in patients with newly diagnosed FLT3 mutation-positive acute myeloid leukemia who were ineligible for intensive chemotherapy: final results of the phase III LACEWING study

Abstract

The phase 3, open-label LACEWING study evaluated efficacy and safety of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (GIL) plus azacitidine (AZA) in newly diagnosed (ND) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy (IIC). Patients were enrolled into a safety cohort (n=15) or randomized (n=168) to GIL+AZA, GIL, or AZA. We present final (6.5-year) outcomes and additional data on mutational subgroups, measurable residual disease (MRD), and pharmacokinetics. Median overall survival (OS) was 9.82 versus 9.23 months (GIL+AZA vs AZA, p=0.182) and 5.24 months (GIL). Corresponding two-year OS rates were 18.8%, 12.9%, and 4.5%. Overall response rates were 70.2% versus 36.8% (GIL+AZA vs AZA, nominal p<0.001) and 72.7% (GIL). Among patients achieving remission, MRD negativity was 30.9%, 30.8%, and 44.4%. Treatment-related adverse event incidence was 12.8, 14.6, and 9.1 events/patient-year. Exploratory analyses demonstrated longer median OS following GIL+AZA versus AZA in patients with FLT3 internal tandem duplications (ITD) without tyrosine kinase domain mutations (11.63 vs 8.87 months, nominal p=0.047), patients with high FLT3-ITD allelic ratio (11.89 vs 7.46 months, nominal p=0.016), and propensity score matched patients without subsequent AML therapy (9.00 vs 3.32 months). Patients with NPM1-mutated AML with/without DMNT3A mutations exhibited trends toward improved OS with GIL+AZA. New RAS/MAPK mutations were identified in 39% of GIL+AZA/GIL patients at relapse. Mean GIL trough concentrations at cycle-1-day-15 for GIL+AZA and GIL were 744 and 650 ng/mL. Although median OS was not significantly different between GIL+AZA and AZA, these results provide valuable insights informing future GIL-based combinations.