FDA Approves Gilteritinib for FLT3+ Acute Myeloid Leukemia

Roxanne Nelson RN, BSN

November 28, 2018

The US Food and Drug Administration (FDA) has approved gilteritinib (Xospata, Astellas Pharma) for the treatment of adult patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

An expanded indication for a companion diagnostic was also granted, to use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc, is used to detect the FLT3 mutation in patients with AML.

"Approximately 25 to 30% of patients with AML have a mutation in the FLT3 gene," 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. "These mutations are associated with a particularly aggressive form of the disease and a higher risk of relapse."

Pazdur added that gilteritinib is the first drug to receive approval that can be used as monotherapy in this population of AML patients.

FLT3 is the most frequently mutated gene that has been identified in AML, and FLT3 internal tandem duplication mutations are associated with high relapse rates, short remissions, and poor survival outcomes. Gilteritinib is a highly selective FLT3 tyrosine kinase inhibitor that has demonstrated activity against FLT3 ITD mutations, and also inhibits FLT3 D835 mutations that can confer clinical resistance to other FLT3 inhibitors.

Improved Outcomes

The approval was based on data from the ADMIRAL study, a randomized phase 3 trial in which 138 adult patients with FLT3-positive relapsed/refractory AML received gilteritinib orally at 120 mg daily. Within this group, 21% of patients achieved a complete remission or complete remission with partial hematologic recovery.

In addition, of the 106 patients who required red blood cell or platelet transfusions at baseline, 31% became transfusion-free for at least 56 days.

The ADMIRAL trial itself is still ongoing, and detailed response and overall survival data are expected to be made public in the coming year.

Results from the CHRYSALIS study, an earlier, first-in-human phase 1/2 trial, involved 252 patients and showed that 49% of patients with relapsed or refractory AML and an FLT3 mutation responded to gilteritinib. The median survival for these participants was more than 7 months. Only 12% of patients without FLT3 mutations responded to gilteritinib, providing evidence that it acts as a selective inhibitor of mutated FLT3. The findings from this early trial were published in Lancet Oncology (Lancet Oncol. 2017;18:1061-1075).

Data from the CHRYSALIS trial also showed that the drug was generally well tolerated, and the most common adverse events attributed to gilteritinib were diarrhea in 41 patients (16%), fatigue in 37 patients (15%), and elevated aspartate aminotransferase and alanine aminotransferase in 33 patients (13%). These were generally mild in severity, and only 25 patients (10%) stopped their treatment because of side effects.

"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," lead investigator 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, in Philadelphia, said in a news release.

In the release, Perl also pointed out that gilteritinib is given in an outpatient setting, making it easier for patients to receive treatment.

"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," Perl said.

In 2017, the FDA granted this application Fast Track and Priority Review designation, and gilteritinib also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

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