Background
Phase 3, open-label, randomized trial in newly diagnosed FLT3 mutation-positive AML in patients ineligible for intensive induction chemotherapy. 15 patients entered a safety cohort and 168 were randomized across three arms (183 total). Gilteritinib is a type I FLT3 inhibitor with activity against both ITD and TKD mutations, already approved in relapsed/refractory FLT3-mutated AML. The hypothesis was that adding gilteritinib to azacitidine would prolong survival in unfit patients. This publication reports the final 6.5-year outcomes plus mutational subgroup, MRD, and pharmacokinetic data; the trial had previously been stopped at a pre-planned interim analysis for futility.
Results
Interventions and follow up: Arm A: Gilteritinib 120 mg PO daily + azacitidine 75 mg/m² SC/IV days 1-7 of each 28-day cycle
Arm B: Gilteritinib 120 mg PO daily (monotherapy)
Arm C: Azacitidine 75 mg/m² days 1-7 of each 28-day cycle
Primary endpoint: Overall survival, gilteritinib + azacitidine vs azacitidine
mFollow up: final analysis at 6.5 years from study start
Results: OS (GIL+AZA vs AZA, primary): 9.82 vs 9.23 mo; P=.182 — primary endpoint not met
OS (gilteritinib monotherapy): 5.24 mo
2-year OS: 18.8% (GIL+AZA) vs 12.9% (AZA) vs 4.5% (GIL)
ORR: 70.2% vs 36.8% (GIL+AZA vs AZA), nominal P value only
MRD and mutational subgroups: reported as exploratory; no subgroup showed an OS advantage that reached formal significance
Arm B: Gilteritinib 120 mg PO daily (monotherapy)
Arm C: Azacitidine 75 mg/m² days 1-7 of each 28-day cycle
Primary endpoint: Overall survival, gilteritinib + azacitidine vs azacitidine
mFollow up: final analysis at 6.5 years from study start
Results: OS (GIL+AZA vs AZA, primary): 9.82 vs 9.23 mo; P=.182 — primary endpoint not met
OS (gilteritinib monotherapy): 5.24 mo
2-year OS: 18.8% (GIL+AZA) vs 12.9% (AZA) vs 4.5% (GIL)
ORR: 70.2% vs 36.8% (GIL+AZA vs AZA), nominal P value only
MRD and mutational subgroups: reported as exploratory; no subgroup showed an OS advantage that reached formal significance
Adverse events
Grade ≥3 (most common): febrile neutropenia 35.6% with gilteritinib + azacitidine; anaemia 27.7% with azacitidine alone
Any-grade, GIL+AZA: pyrexia 47.9%, diarrhoea 38.4%, febrile neutropenia 35.6%, constipation 34.2%, nausea 32.9%
Any-grade, AZA: pyrexia 34.0%, anaemia 34.0%, neutropenia 27.7%, thrombocytopenia 23.4%
Note: AE rates are from the LACEWING safety population as reported in the primary analysis (Wang et al, Blood 2022); the final report adds no new safety signal
Any-grade, GIL+AZA: pyrexia 47.9%, diarrhoea 38.4%, febrile neutropenia 35.6%, constipation 34.2%, nausea 32.9%
Any-grade, AZA: pyrexia 34.0%, anaemia 34.0%, neutropenia 27.7%, thrombocytopenia 23.4%
Note: AE rates are from the LACEWING safety population as reported in the primary analysis (Wang et al, Blood 2022); the final report adds no new safety signal
Conclusions
Gilteritinib plus azacitidine roughly doubled the response rate versus azacitidine alone (70.2% vs 36.8%) but did not translate into an overall survival benefit (9.82 vs 9.23 months, P=.182), and the trial was stopped for futility. Gilteritinib monotherapy was clearly inferior (median OS 5.24 months) and should not be used as frontline therapy in this population. LACEWING is a cautionary example of a large ORR gain failing to move survival in unfit AML.
Key Limitations
Open-label design and early termination for futility at a pre-planned interim analysis, so the final analysis is underpowered for OS and for every subgroup. The most important limitation is comparator drift: LACEWING randomised against azacitidine monotherapy, but VIALE-A (2020) established azacitidine + venetoclax as the standard for unfit AML during the trial's conduct, so the control arm no longer reflects contemporary care and the trial cannot tell us whether adding gilteritinib to azacitidine + venetoclax helps. There was no venetoclax-containing arm. Mutational subgroup, MRD, and pharmacokinetic analyses are exploratory and hypothesis-generating only. The gilteritinib monotherapy arm was small and its inferiority was evident early.
Clinical Context
Gilteritinib is FDA- and EMA-approved for relapsed/refractory FLT3-mutated AML on the basis of ADMIRAL, and is not approved as frontline therapy for unfit patients. LACEWING closes the door on gilteritinib + azacitidine as a frontline doublet. For newly diagnosed FLT3-mutated AML in patients unfit for intensive chemotherapy, NCCN and ESMO recommend azacitidine + venetoclax as the backbone; the triplet of azacitidine + venetoclax + gilteritinib is supported by promising phase 1/2 data and is under prospective evaluation but is not yet a guideline standard. For fit patients, FLT3 inhibitors added to intensive induction (midostaurin per RATIFY, quizartinib per QuANTUM-First) remain the standard.