Phase 3 Trial of Gilteritinib Plus Azacitidine Vs Azacitidine for Newly Diagnosed FLT3mut+ AML Ineligible for Intensive Chemotherapy.

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to gilteritinib (120 mg/day orally) and azacitidine (GIL+AZA) or azacitidine (AZA) alone. The primary endpoint was overall survival (OS). At the interim analysis (26 August 2020), 123 patients were randomized (GIL+AZA, n=74; AZA, n=49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL+AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL+AZA) and 8.87 (AZA) months (HR 0.916 [95% CI: 0.529, 1.585]; P=0.753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival (EFS) was 0.03 months in both arms. EFS defined using composite CR (CRc) was 4.53 (GIL+AZA) and 0.03 (AZA) months (HR 0.686 [95% CI: 0.433, 1.087]; P=0.156). CRc rates were 58.1% (GIL+AZA) and 26.5% (AZA; difference 31.4% [95% CI: 13.1, 49.7]; P<0.001). Adverse event (AE) rates were similar for GIL+AZA (100%) and AZA (95.7%) and grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL+AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady state trough concentrations were no different between GIL+AZA and gilteritinib. GIL+AZA resulted in significantly higher CRc rates although similar OS versus AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL+AZA in older/unfit patients with FLT3mut+ AML. Clinical Trial # NCT02752035