Treatment with gilteritinib, an oral, potent, selective FLT3 inhibitor led to higher percentages of patients with response and longer survival than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated acute myeloid leukaemia (AML). The main toxicity was myelosuppression. A small signal regarding hepatic toxic effects bears attention in future studies. The results from thephase III trial were published by Prof. Alexander E. Perl of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA and colleagues on 31 October 2019 in The New England Journal of Medicine.
Patients with relapsed or refractory AML have a dismal prognosis with standard chemotherapy. FLT3-activating mutations occur in approximately 30% of patients with AML, primarily as in-frame internal tandem duplications (ITD) within the juxtamembrane region or as missense point mutations in the tyrosine kinase domain (TKD). In patients with AML, the presence of the FLT3 ITD mutation adversely affects survival, both at diagnosis and on failure of the initial therapy.
Several FLT3 tyrosine kinase inhibitors, either under development or approved for the treatment of AML, vary in kinase selectivity, potency, and clinical activity.
Gilteritinib is a new, highly selective, oral FLT3 inhibitor with activity against both FLT3 mutation subtypes (ITD and TKD) and weak activity against c-Kit. Gilteritinib also inhibits the tyrosine kinase AXL, which is implicated in FLT3 inhibitor resistance.
In a phase I/II study, single-agent gilteritinib resulted in sustained inhibition of FLT3 autophosphorylation. At doses of at least 80 mg per day, it led to 41% of the patients with relapsed or refractory FLT3-mutated AML having a composite complete remission. A starting dose of 120 mg per day was recommended for further study.
In this phase III study, the investigators randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib or salvage chemotherapy. The two primary endpoints were overall survival and the percentage of patients who had complete remission with full or partial haematologic recovery. Secondary endpoints included event-free survival and the percentage of patients who had complete remission.
Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group.
The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group, 9.3 months versus 5.6 months (hazard ratio [HR] 0.64; p < 0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (HR 0.79). The percentage of patients who had complete remission with full or partial haematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points).
In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group. The most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anaemia (40.7%), thrombocytopenia (22.8%).
Drug-related adverse events leading to the discontinuation of gilteritinib occurred in 27 patients (11.0%); the most common events were elevated aspartate aminotransferase level (1.6%), elevated alanine aminotransferase level (1.2%), and pneumonia (1.2%).
The authors concluded that gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.
The study was funded by Astellas Pharma.
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med 2019; 381:1728-1740.