By Megan Brooks
NEW YORK (Reuters Health) - 2/4/2019
Treatment with the FLT3 inhibitor gilteritinib (Xospata) improves survival for patients with relapsed or refractory acute myeloid leukemia (AML) harboring an FLT3 mutation compared with standard salvage chemotherapy, according to final results of the phase 3 ADMIRAL clinical trial.
The FLT3 gene is mutated in about one-third of patients diagnosed with AML in the U.S. Patients with relapsed or refractory FLT3-mutated AML have a particularly "dismal" prognosis, Dr. Alexander Perl said during an April 1 briefing with reporters at the American Association for Cancer Research (AACR) annual meeting in Atlanta, where the findings were presented.
The U.S. Food and Drug Administration (FDA) approved gilteritinib for FLT3-mutated relapsed or refractory AML last year based on safety data and an interim analysis of the rate of response to the drug in the ADMIRAL trial. The approval was not based on a comparison of the efficacy of gilteritinib relative to standard chemotherapy, Dr. Perl of the University of Pennsylvania Perelman School of Medicine in Philadelphia points out in an AACR news release.
The ADMIRAL trial was an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in 371 patients with FLT3-mutated AML refractory to first-line AML therapy or who had relapsed after first-line therapy.
Of these, 247 patients were randomly assigned to gilteritinib (120 mg/d) and 124 to standard salvage chemotherapy, which included investigator's choice of low-dose cytarabine; azacitidine; mitoxantrone, etoposide, and cytarabine; and fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin.
Overall survival, the primary end point, was "statistically significantly better" with gilteritinib than with salvage chemotherapy, Dr. Perl told the briefing.
Median overall survival was 9.3 months with gilteritinib versus 5.6 months with salvage chemotherapy, a 36% reduction in the risk of death (hazard ratio, 0.637; P=0.007). The one-year survival rate was 37% with gilteritinib therapy versus 17% with salvage chemotherapy.
"The longest survival in the gilteritinib arm was seen among patients who proceeded to (hematopoietic stem cell) transplant and then resumed gilteritinib thereafter to prevent relapse, but unfortunately long-term survival was very uncommon on either treatment arm," Dr. Perl said in the release. "In an effort to further improve long-term outcomes, clinical trials testing gilteritinib in combination with other therapies for relapsed or refractory FLT3-mutated AML and testing gilteritinib as frontline therapy for newly diagnosed patients have already been launched."
Gilteritinib was generally well tolerated with no "important safety signal that was concerning in terms of serious frequent toxicities," Dr. Perl reported.
The most common side effects seen in the first month of treatment were anemia (33%), increased alanine aminotransferase (24%), increased aspartate aminotransferase (24%), febrile neutropenia (21%), thrombocytopenia (19%), constipation (17%), pyrexia (15%), fatigue (15%), decreased neutrophil count (14%), increased blood alkaline phosphatase (13%), nausea (13%), hypokalemia (11%), cough (11%), headache (10%), and diarrhea (10%).
Results from the ADMIRAL trial demonstrating relatively low toxicity and improved overall survival compared with standard salvage chemotherapy are "practice-changing" and establish "gilteritinib as a new standard of care" for patients with FLT3-mutated refractory or relapsed AML, Dr. Perl told the briefing.
Briefing moderator Dr. Louis Weiner of the Georgetown Lombardi Comprehensive Cancer Center, agreed. Gilteritinib is a "new practice-changing strategy and something that we've been needing in the field of acute myelogenous leukemia therapy for the entire time I've been an oncologist," he told the briefing.
The study was funded by Astellas Pharma US Inc. Dr. Perl has received honoraria for serving on advisory boards for Astellas as well as consultancy fees from the company.
AACR 2019 Annual Meeting.