FDA Approves Gilteritinib for FLT3+ AML

The FDA has approved gilteritinib for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory acute myeloid leukemia.

The FDA has approved gilteritinib (Xospata) for the treatment of adult patients with FLT3 mutation—positive relapsed or refractory acute myeloid leukemia (AML).

The approval of the FLT3 inhibitor was based on data from the ADMIRAL study, in which 138 adult patients with FLT3-positive relapsed/refractory AML received gilteritinib orally at 120 mg daily. The rate of complete remission (CR) or CR with partial hematologic recovery (CRh) was 21% (n = 29; 95% CI, 14.5-28.8) at a median follow-up of 4.6 months.1

During any 56-day post-baseline period, 33 (31.1%) of the 106 patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline became independent of such transfusions. Seventeen (53.1%) of the remaining 32 patients who were RBC/platelet-transfusion independent at baseline remained independent of transfusion during any 56-day post-baseline period.

"Today's approval brings a new, highly-effective, and well-tolerated treatment option to the clinic for a group of truly high-risk patients who, until today, had no specific therapies available beyond chemotherapy to treat their disease," gilteritinib clinical researcher Alexander Perl, MD, an associate professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center, said in a statement.

The 138 AML patients reviewed for efficacy had a FLT3 ITD, D835, or I836 mutation as detected by the LeukoStrat CDx FLT3 Mutation Assay. Along with the approval of gilteritinib, the FDA expanded the indication for this companion diagnostic to include use with the FLT3 inhibitor.

The median patient age was 60 years, including 85 patients who were aged <65 years and 53 patients who were aged ≥65 years. Forty-six percent of patients were male and 54% were female. The baseline ECOG performance status was 0-1 for 82% of patients and ≥2 for 18% of patients.

Fifty-nine percent of patients had untreated relapse AML and 41% had primary refractory AML. The median number of relapses was 1. Twenty percent of patients had prior stem cell transplantation. Regarding FLT3 mutation status, 121 patients had ITD alone, 12 patients had TKD alone, and 5 patients had ITD and TKD.

“Approximately 25% to 30% of patients with AML have a mutation in the FLT3 gene. These mutations are associated with a particularly aggressive form of the disease and a higher risk of relapse,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Xospata targets this gene and is the first drug to be approved that can be used alone in treating patients with AML having a FLT3 mutation who have relapsed or who don’t respond to initial treatment.”

According to the FDA, adverse events (AEs) occurring in at least 20% of patients receiving gilteritinib included myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness, and vomiting.

"Although we're waiting for the final analysis of ADMIRAL, the available data with gilteritinib show fewer and milder side effects than typically is seen with traditional chemotherapy," said, Perl, adding, "Often, salvage therapy is used to stabilize aggressive leukemia before a patient receives a bone marrow transplant that we hope can be curative. Having a low-toxicity but highly-active drug like gilteritinib means that relapsed or refractory patients not only are more likely to undergo transplant, but also they remain stronger at the time of transplant and are better able to withstand the surgery and recovery."

In October 2017, the FDA granted Fast Track designation to gilteritinib for use in this setting. The designation, which is designed to accelerate the development, review, and approval of drugs that treat serious and life-threatening conditions, was based on early-stage research with the FLT3 inhibitor.

In results from a phase I/II dose-escalation (n = 23) and dose-expansion (n = 229) study published in The Lancet Oncology, investigators concluded that the maximum-tolerated dose of gilteritinib was 300 mg daily and determined that the treatment was generally well tolerated.2 Among patients included in the safety analysis (n = 252), the most common grade 3/4 AEs were febrile neutropenia (39%), anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

The most common treatment-related AEs were similar to those associated with other AML drugs: diarrhea, fatigue, elevated aspartate aminotransferase, and increased alanine aminotransferase. Ten percent of patients required dose reductions, most commonly for diarrhea (1%) or fatigue (1%).

Serious AEs were relatively rare. The most common (≥5%) included febrile neutropenia (39%), sepsis (14%), pneumonia (11%), acute renal failure (10%), pyrexia (8%), bacteremia (6%), and respiratory failure (6%). Only febrile neutropenia, acute renal failure, pyrexia, sepsis, and bacteremia were determined to be treatment-related.

From October 2013 to August 2015, a total of 265 patients enrolled in the study. By November 2015, 88% had discontinued treatment and 12% remained on-study. Median treatment duration was 25.9 weeks.

Investigators locally confirmed internal tandem duplication mutations in FLT3 in 162 patients at screening. Thirteen patients had a point mutation in the D835 codon and 16 had both types of FLT3 mutation. All 31 patients who remained on treatment after November 2015 had an internal tandem duplication mutation in FLT3.

Patients in the dose-escalation phase were assigned to 1 of 7 gilteritinib daily dosing regimens, from 20 mg to 450 mg. Investigators established the 300 mg per day schedule as the maximum-tolerated dose after 2 of 3 patients in the 450-mg cohort experienced dose-limiting grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.

Of 75 patients who achieved a composite CR, 2 (1%) received the 20 mg/day dose, 7 (3%) received the 80 mg/day dose, 27 (11%) received the 120 mg/day dose, 36 (14%) received the 200 mg/day dose, and 3 (1%) received the 300 mg/day dose. The median duration of response was 17 weeks (95% CI, 14-29).

The research team observed antidisease activity at all dose levels. Of the 249 patients included in the full analysis, 40% had a response to treatment including 19 (8%) who had a CR, 10 (4%) had CR with incomplete platelet recovery, 46 (18%) had CR with incomplete hematological recovery, and 25 (10%) had partial remission.

Concentrations in plasma of gilteritinib after oral daily dosing were generally dose-proportional and showed substantial accumulation until steady-state levels at treatment day 15. Investigators noted potent target inhibition at all dose levels, prompting expansion of all dose cohorts ranging from 20 mg/day to 300 mg/day.

Exposure-related inhibition of FLT3 phosphorylation increased along with increasing gilteritinib concentrations in plasma. Most patients receiving a daily dose of 80 mg or higher had at least 90% of FLT3 phosphorylation inhibition by day 8. In-vivo inhibition of FLT3 occurred at all dose levels.


  1. FDA Prescribing Information: XOSPATA® (gilteritinib) tablets, for oral use. Accessed November 28, 2018. https://bit.ly/2SjB8CL.
  2. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1—2 study. Lancet Oncol. 2017;18:1061-1075

The CR rate was 11.6% (n = 16) and the CRh rate was 9.4% (n = 13). The median time to first response was 3.6 months (range, 0.9-9.6) among patients reaching CR/CRh.

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