Already in December 2020, a review by an Independent Data Monitoring Committee of the phase III LACEWING study determined that the combination of gilteritinib and azacitidine was unlikely to improve the overall survival (OS) compared to azacitidine alone in patients newly diagnosed FLT3-positive acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy and decided to stop patient enrolment. Earlier this year, Blood finally published a more complete overview of the results of this trial. Although OS data were similar between patients treated with or without gilteritinib alongside azacitidine, in patients with a high FLT3-ITD allelic burden (allelic ratio ≥0.5), gilteritinib did improve the median OS by 6.3 months, deserving further investigation.
Patients with newly diagnosed acute myeloid leukaemia (AML) who are considered unfit for standard intensive induction chemotherapy face a worse survival prospect and a worse treatment response than their fitter counterparts. Activated FLT3 with an internal tandem duplication (ITD) and FLT3 tyrosine kinase domain (TKD) mutations are found in up to 35% and 14% of AML cases, respectively and the presence of these genetic alterations is associated with worse a survival. Interestingly, in patients with FLT3-mutated AML who are deemed ineligible for intensive chemotherapy, the combination of a FLT3 inhibitor with hypomethylating agents (i.e., azacitidine or decitabine) has shown synergistic cytotoxicity. Gilteritinib is a FLT3 inhibitor with proven efficacy/safety in patients with FLT3-mutated relapsed/refractory (R/R) AML. In the randomised phase III LACEWING study, untreated adults with FLT3-mutated AML ineligible for intensive induction chemotherapy were randomly assigned to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone.
The randomised, open-label, phase 3 LACEWING study compared the efficacy and safety of GIL + AZA vs. AZA alone in patients with newly-diagnosed FLT3 mutated AML ineligible for intensive induction chemotherapy coming from ~185 centres in North America, Europe, and Asia/Pacific. Ineligibility for intensive induction chemotherapy was defined as an age ≥65 years or patients of any age with selected comorbidities including heart failure, an ECOG performance status ≥2 and malignancies not requiring concurrent treatment. Patients were initially randomised (1:1:1) to receive GIL + AZA (GIl 120 mg/d orally and AZA 75 mg/m2 per day SC or IV on days 1-7), AZA 75 mg/m2 per day SC/IV on days 1 to 7, or GIL 120 mg/d orally. However, the gilteritinib monotherapy arm was removed after about 12 months due to changes in preferred treatment for this patient population (i.e., combination over monotherapy). Patients were subsequently randomised (2:1) to receive GIL + AZA or AZA; both regimens were administered on a 28-day cycle. The primary endpoint of the trial was OS, with a key secondary objective of event-free survival (EFS), defined as time from randomisation until date of documented relapse from complete remission (CR), treatment failure (failure to achieve CR within 6 treatment cycles), or death from any cause, whichever occurred first.
Enrolment in this study was discontinued for futility based on OS results. As of August 26, 2020, a total of 123 patients were randomised (2:1) to receive either gilteritinib plus azacitidine or azacitidine. Of note, nearly three-quarters of patients in each treatment group were aged ≥75 years. The median OS was reported at 9.82 months for the gilteritinib plus azacitidine arm, which was fairly similar to the 8.87 months median OS ween with azacitidine alone (HR[95%CI]: 0.916[0.529–1.585]; p= 0.753). A subsequent subgroup analysis did reveal a trend for a better OS with gilteritinib plus azacitidine over azacitidine alone in patients with an ECOG performance status of 0–1 (13.17 vs. 11.89 months; HR[95%CI]: 0.811[0.409–1.608]) and in the subgroup of patients with a FLT3-ITD allelic ratio of ≥0.5 (10.68 vs. 4.34 months; HR[95%CI]: 0.580[0.285–1.182]) In contrast, patients with FLT3-TKD mutations actually had a shorter OS when they were treated with gilteritinib plus azacitidine compared to azacitidine alone (4.86 vs. 11.89 months; HR[95%CI]: 2.504[0.746–8.411]).
The median EFS was reported at 0.03 months in both arms. The EFS defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (HR[95%CI]: 0.686[0.433-1.087]; p= 0.156). Also the complete remission (CR) rates were similar between the two arms at 16.2% with gilteritinib plus azacitidine and14.3% with azacitidine alone. In contrast, CRc rates were higher in patients who received gilteritinib plus azacitidine at 58.1%, compared with 26.5% for azacitidine (p < 0.001). Within the FLT3 subgroups, CRc rates were highest in patients who received gilteritinib plus azacitidine with FLT3-ITD allelic ratio ≥0.5 (71.4% vs. 20.8%; p = 0.003). Of the 12 patients who achieved CR in the gilteritinib plus azacitidine treatment arm, ten remained in CR, while the median CR duration was 8.57 months for the seven patients who obtained a CR with azacitidine alone.
The adverse event rates were 100% and 95.7% in the gilteritinib plus azacitidine and azacitidine alone arms, respectively. The AEs leading to death were considered treatment related in four patients in each group. Gastrointestinal haemorrhage and QT prolongation were identified as AEs of special interest and occurred in 12.3% and 13.7% of patients in the gilteritinib plus azacitidine treatment group, and in 6.4% and 0% of patients in the azacitidine treatment group.
Although OS data were similar between patients treated with or without gilteritinib alongside azacitidine, in those with high FLT3-ITD allelic burden (allelic ratio ≥0.5), gilteritinib did improve the OS by 6.3 months. Furthermore, CRc rates were significantly higher in the gilteritinib plus azacitidine arm. The safety profile of gilteritinib in combination with azacitidine was consistent with the profiles of each individual therapy. As such, the LACEWING trial demonstrated the safety and favourable clinical activity of gilteritinib plus azacitidine in previously untreated patients with FLT3-mutated AML who are considered unfit for intensive induction chemotherapy. In particular, patients with FLT3-ITD AML and a high allelic burden benefitted most from gilteritinib plus azacitidine, which should be investigated further.
1. Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845-57.