Gilteritinib Approaches EU Approval for FLT3-Mutant AML

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of gilteritinib as a single agent for the treatment of adult patients with relapsed/refractory acute myeloid leukemia who have FLT3 mutations.

Andrew Krivoshik, MD, PhD

The European Medicines Agency's Committee for Medicinal Products for Human Use has recommended approval of gilteritinib (Xospata) as a single agent for the treatment of adult patients with relapsed/refractory acute myeloid leukemia (AML) who have FLT3 mutations.1

The positive opinion is based on results from the phase III ADMIRAL trial, in which the median overall survival (OS) in patients who were treated with gilteritinib was 9.3 months (95% CI, 7.7-10.7) compared with 5.6 months in those who received salvage chemotherapy (95% CI, 4.7-7.3), which translated to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.490-0.830; P = .0004).2 The 1-year OS rates were 37% and 17% for gilteritinib and chemotherapy, respectively.

"The data are encouraging, showing a significant improvement in OS, and 1-year survival rates doubled when comparing gilteritinib to the current standard of care," study investigator Giovanni Martinelli, MD, Institute of Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy, stated in a press release. "For relapsed or refractory FLT3 mutation—positive AML patients the current prognosis is poor, with median OS of less than 6 months following treatment with salvage chemotherapy. If approved by the [European Commission], gilteritinib has the potential to change the treatment landscape."

In the international, phase III ADMIRAL study, 371 adult patients with FLT3-mutant relapsed/refractory AML were randomized 2:1 to receive gilteritinib at 120 mg daily (n = 247) or salvage chemotherapy (n = 124). Patients in both arms then underwent hematopoietic stem cell transplantation (HSCT), but only patients in the gilteritinib arm then resumed treatment with the FLT3 inhibitor; crossover was not permitted. Additionally, salvage chemotherapy was selected prior to randomization and could be one of the following regimens: mitoxantrone, etoposide, and cytarabine; fludarabine, cytarabine, idarubicin, and G-CSF; low-dose cytarabine; and azacitidine.

To be eligible for enrollment, patients with AML must have also harbored a FLT3-ITD or FLT3-TKD mutation, a mean of triplicate Fridericia-corrected QT interval <450 milliseconds at screening based on central reading, and be refractory to induction chemotherapy or in untreated first relapse.

Baseline characteristics were comparable between arms. Overall, the median age was 62 (range, 19-85) and 54% of patients were female. The majority of patients had intermediate-risk cytogenetics (73%) and 88% of patients had FLT3-ITD mutations. Additionally, 20% of patients had underwent prior HSCT, and 82% had received upfront intensive chemotherapy. Thirty-nine percent of patients had primary refractory AML without HSCT and 27% relapsed ≤6 months after composite complete remission (CRc).

The coprimary endpoints were OS and CR/CRh rate; secondary endpoints were event-free survival, CR rate, leukemia-free survival, duration of remission (DOR), CRc rate, transplantation rate, brief fatigue inventory, CRh rate, transfusion conversion rate, and transfusion maintenance rate.

Results showed that the complete remission (CR)/complete remission with partial hematologic recovery (CRh), CR with incomplete hematologic recovery, and CR with incomplete platelet recovery rates with gilteritinib compared with salvage chemotherapy were 21% versus 11%, 13% versus 5%, 26% versus 11%, and 8% versus 0%, respectively. Additionally, the CRc rate was 54% with gilteritinib and 22% with salvage therapy.

The overall response rates were 26% with salvage chemotherapy and 68% with gilteritinib, which comprised a 13% partial response rate.

Moreover, the median duration of gilteritinib exposure was significantly longer than that of salvage therapy, at 4.1 months (range, 0.1-29.1) and 0.9 months (range, 0.2-7.1), respectively. The median time to achieve CRc was 1.8 months (95% CI, 0.9-9.95) with gilteritinib and 1.1 months (95% CI, 0.8-2.9) with salvage treatment. The median DOR with gilteritinib was also significantly longer at 11.0 months compared with 1.8 months with salvage therapy.

Regarding safety, gilteritinib's tolerability profile is based on 319 patients with relapsed/refractory AML in 3 clinical trials: NCT02421939, NCT02014558, and NCT02181660.

Adverse events (AEs) that led to death occurred in 2% of patients on gilteritinib, which included cardiac arrest (1%) and differentiation syndrome and pancreatitis (n = 1 case each). The most frequent (≥5%) nonhematological serious AEs were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%). Moreover, the most frequent (≥5%) grade ≥3 nonhematological AEs reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

"There is a high unmet need in AML and Astellas is committed to improving treatment options. Gilteritinib offers a potential new alternative for patients with relapsed or refractory FLT3mut+ AML, with data showing improved survival outcomes," Andrew Krivoshik, MD, PhD, senior vice president and Global Therapeutic Area Head, Oncology Development, Astellas, the developer of gilteritinib, stated in the press release. "Subject to EC approval, gilteritinib has the potential to provide new hope for clinicians, patients and their families."

Gilteritinib was initially approved by the FDA in November 2018; the decision was based on an interim analysis of CR/CRh rate, duration of CR/CRh, and rate of conversion from transfusion dependence to transfusion independence. The label was updated in May 2019 to include the OS data from the ADMIRAL trial.


  1. Astellas receives positive CHMP opinion for Xospata® (gilteritinib) as a monotherapy for patients with relapsed or refractory acute myeloid leukemia with a FLT3 mutation. Astellas Pharma. Published September 20, 2019. Accessed September 20, 2019.
  2. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the Phase III ADMIRAL trial. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CTPL04.