Abstract
Final results from the phase III ADMIRAL trial indicate that the FLT3/AXL tyrosine kinase inhibitor gilteritinib extends overall survival and improves remission rates in patients with relapsed/refractory, FLT3-mutant acute myeloid leukemia compared with standard chemotherapy. The results suggest that gilteritinib, which was FDA-approved in November 2018, should become the new standard of care.
Last fall, the FDA approved gilteritinib (Xospata; Astellas Pharma) for relapsed/refractory, FLT3-mutant acute myeloid leukemia (AML) based on interim data from the phase III ADMIRAL trial. Final results presented on April 1 at the American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA, indicate that the drug significantly extended overall survival (OS) and more than doubled remission rates compared with chemotherapy—with less toxicity. These findings, along with the approval, establish gilteritinib as the new standard of care, according to clinicians.
Typically treated with intensive chemotherapy, FLT3-mutated AML is an aggressive form of the disease that occurs in 25% to 30% of patients, said Alexander Perl, MD, of the University of Pennsylvania in Philadelphia, who presented the results. A FLT3/AXL tyrosine kinase inhibitor (TKI), “gilteritinib was developed because it was active against both FLT3 internal tandem duplication (ITD) mutations that are associated with relapse and FLT3 tyrosine kinase domain (TKD) mutations that commonly arise during therapy with other FLT3 TKIs and confer drug resistance,” Perl said.
In the ADMIRAL trial, 247 patients with relapsed/refractory AML who had ITD and/or TKD FLT3 mutations received gilteritinib or one of four standard chemotherapy options. Patients treated with gilteritinib had a median OS of 9.3 months, a 1-year survival rate of 37.1%, and a remission rate of 34% (complete remission plus complete remission with partial hematologic recovery), compared with 5.6 months, 16.7%, and 15.3%, respectively, in patients who received chemotherapy. Serious side effects—corrected for duration of therapy—occurred in 7.1% of patients receiving gilteritinib, compared with 9.2% of patients on chemotherapy.
“This is a change in terms of how we approach patients with aggressive relapsed/refractory disease, because we can get better results from less toxic, mutation-targeted therapy,” Perl said, adding that he thinks testing for FLT3 mutations should become standard for all patients with relapsed/refractory AML. Now, trials are combining gilteritinib with other drugs to treat newly diagnosed and relapsed/refractory disease.
“Gilteritinib went up against investigator/patient's choice—which included many patients receiving intensive chemotherapy—in the second line and won on all fronts: survival, response rate, toxicity,” said Ross Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the trial. “I think these data and the approval establish this as the treatment of choice for FLT3-mutant AML in the relapsed/refractory setting.”
However, Levine emphasized that gilteritinib alone is not a cure for AML. Additional research, such as studies combining gilteritinib with an IDH inhibitor to treat patients with multiple mutations, is needed. “I think of this as not the kind of success we want to ultimately end with,” Levine said, “but rather a block on which we can build toward curative regimens.” –Catherine Caruso