Gilteritinib Labeling to Include Overall Survival Data After FDA Approval

FDA approved addition of OS to labeling based on results of the ADMIRAL trial.

Gilteritinib, a treatment for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation, has received an approval from the US Food and Drug Administration (FDA) for the addition of overall survival (OS) data in labeling.

The FDA approval was based on the results of the ADMIRAL trial (NCT02421939), which demonstrated improvement in Overall Survival in those treated with gilteritinib.

"The ADMIRAL trial's Overall Survival findings are encouraging for patients and families impacted by relapsed/refractory FLT3 mutation-positive AML," said Alexander Perl, MD, of Abramson Cancer Center, University of Pennsylvania. "The data underscore the importance of single-agent XOSPATA for this patient population that, until recently, had few remaining treatment options."

The ADMIRAL trial included 371 adult patients with relapsed or refractory AML patients and a FLT3 ITD, D835, or I836 mutation by the LeukoStrat CDx FLT3 Mutation Assay. The purpose of the trial was to compare the clinical benefit of gilteritinib to salvage chemotherapy, through an assessment of OS, and determine the efficacy of gilteritinib by examining the rate of complete remission (CR) and complete remission with partial hematological recovery(CRh) in these patients.

Patients were randomized at a 2:1 ratio to receive gilteritinib 120mhg once per day over continuous 28-day cycles or pre-specified salvage chemotherapy. A total of 247 were included in the gilteritinib group and 124 in the salvage chemotherapy group. Salvage chemotherapy included either intensive cytotoxic chemotherapy or a low-intensity regimen.

OS was measured from randomization until death by any cause. The median OS in the gilteritinib group was 9.3 months and 5.6 months for those in the chemotherapy group (HR 0.64; 95% CI: 0.49,0.83; 1 sided P=0.0004). The results were consistent in those receiving intensive cytotoxic chemotherapy (HR 0.66; 95% CI: 0.47-0.93) and those receiving a low-intensity regimen (HR 0.56; 95% CI: 0.38-0.84). The other endpoints of CR and CRh in the gilteritinib group at the interim analysis was 21% (95% CI: 14.5, 28.8).

Fatal adverse reactions occurred in 2% of patients receiving gilteritinib during the trial. These included cardiac arrest (1%) and one case each of pancreatitis and differentiation syndrome. Nonhematological serious adverse reactions reported in patients at a frequency greater than 5% were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%), and noninfectious diarrhea. The most frequent (5% or greater) grade 3 or higher non-hematological adverse reactions reported were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

"Delivering innovation and value to address the unmet medical needs of patients is at the core of everything we do," said Bernhardt G. Zeiher, MD, chief medical officer at Astellas. "The FDA's approval of the sNDA based on Overall Survival data further highlights the strong potential XOSPATA has to help patients suffering from FLT3 mutation-positive AML, a life-threatening disease."

The original FDA approval for gilteritinib in Nov. 2018 was based on an interim analysis of the ADMIRAL trial based on different endpoints. Those endpoints included he rate of complete remission and complete remission with partial hematologic recovery, the duration of CR and CRh, and the rate of conversion from transfusion dependence to transfusion independence.

Prescribing information for gilteritinib includes a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome, which may be life-threatening or fatal if not treated.