Addition of gilteritinib to azacitidine may benefit certain patients with FLT-mutated AML
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Gilteritinib plus azacitidine conferred significantly higher complete remission rates, but similar OS, vs. azacitidine among patients with newly diagnosed, FLT3-mutated acute myeloid leukemia ineligible for intensive induction chemotherapy.
Results of the randomized phase 3 study presented at ASH Annual Meeting and Exposition showed the greatest benefit with gilteritinib (Xospata, Astellas Pharma) added to azacitidine among patients with ECOG performance status of 0 to1 and high FLT3-ITD allelic ratio. Researchers reported no new safety signals.
“Patients with FLT3-mutant AML who are unable to receive intensive chemotherapy have limited therapeutic options and short overall survival. Treatment outcomes with hypomethylating agents commonly used to treat these patients, such as azacytidine, are modest,” Eunice S. Wang, MD, chief of the leukemia service, medical director of infusion services and professor of oncology at Roswell Park Comprehensive Cancer, told Healio. Gilteritinib, a next-generation FLT3 tyrosine kinase inhibitor, received FDA approval as monotherapy based on results of the randomized phase 3 ADMIRAL trial, in which it demonstrated superior efficacy, as well as safety and tolerability, compared with chemotherapy for patients with relapsed or refractory FLT3-mutant AML, Wang said.
“In preclinical mouse models, encouraging anti-leukemia activity was observed with the combination of gilteritinib and azacitidine,” Wang added. “Therefore, the LACEWING trial was designed to compare the efficacy and safety of gilteritinib plus azacitidine vs. azacitidine alone in patients with newly diagnosed FLT3-mutant AML who are unable to receive intensive induction chemotherapy.”
The analysis included 123 patients who were randomly assigned to gilteritinib plus azacitidine (n = 74; median age, 78 years; ECOG performance status 2, 47.3%) or azacitidine alone (n = 49; median age, 76 years; ECOG performance status 2, 32.7%).
Patients in the combination group received 120 mg gilteritinib orally each day on days 1 to 28 plus azacitidine dosed at 75 mg/m2 per day subcutaneous/IV on days 1 to 7. Patients in the azacitidine monotherapy group received the same azacitidine regimen.
The randomization date served as the treatment failure date if complete remission was not achieved after six cycles.
OS served as the primary endpoint, with EFS as a key secondary endpoint. Researchers also analyzed response rates, safety/tolerability and pharmacokinetic endpoints and performed prespecified subgroup/sensitivity analysis. They obtained long-term follow-up of 3 or more years, including subsequent AML therapy.
Median follow-up was 9.76 months for the gilteritinib-azacitidine group and 17.97 months for the azacytidine group.
Results of an interim analysis after 70 deaths showed median OS of 9.82 months with gilteritinib plus azacitidine and 8.87 months with azacitidine (HR = 0.916; 95% CI, 0.529-1.585).
“Confounding factors may have been higher numbers of patients in the gilteritinib-plus-azacitidine group with worse performed status and the confounding effects of subsequent AML therapy, which included FLT3 inhibitors (specifically gilteritinib) in patients in the azacitidine-alone group,” Wang told Healio.
Researchers observed improved OS with the combination therapy in subgroups of patients with ECOG performance status of 0 to 1 (HR = 0.81; 95% CI, 0.4-1.6) and those with high FLT3-ITD allelic ratio of 0.5 or greater (HR = 0.58; 95% CI, 0.28-1.18).
Median EFS was 0.03 months in both groups (HR = 1.17; 95% CI, 0.76-1.8). And in sensitivity analyses, median EFS — with events based on composite complete response — was 5.03 months for gilteritinib plus azacitidine and 3.29 months for azacitidine (HR = 0.92; 95% CI, 0.57-1.48).
Composite complete response rates were significantly higher with the combination (58.1% vs. 26.5%), a difference of 31.4% (95% CI, 13.1-49.7), despite similar complete response rates for both groups (16.2% vs. 14.3%).
Trough concentrations at steady-state values were twofold greater in patients with newly diagnosed FLT3-mutation-positive AML ineligible for intensive induction chemotherapy than in patients with relapsed or refractory AML.
The gilteritinib-azacitidine and azacitidine groups had similar rates of overall adverse events (100% vs. 95.7%) and grade 3 or greater adverse events (95.9% vs. 89.4%). Four patients in each group died of treatment-related adverse events. Among the common adverse events with gilteritinib plus azacitidine were pyrexia (47.9%) and diarrhea (38.4%).
“We believe these results support continued examination of the safety and activity of gilteritinib plus azacitidine in patients with FLT3-mutant AML,” Wang said.
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Wang ES, et al. Abstract 700. Presented at: ASH Annual Meeting and Exposition. Dec. 11-14, 2021; Atlanta.
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