ATLANTA—The FLT3 inhibitor gilteritinib provided better survival outcomes than standard chemotherapy in patients with relapsed or refractory acute myeloid leukemia (RR-AML) carrying the FLT3 mutation, according to final results from a phase III clinical trial, presented at the American Association for Cancer Research annual meeting (Abstract CT184).
The FDA approved gilteritinib tablets in November after reviewing safety and interim response data among patients enrolled in the ADMIRAL trial, but survival data were not mature at that time. Gilteritinib became the first monotherapy to be approved for this population of AML patients. At the same time, the agency also approved a special assay for the mutation.
Final analysis showed a significant survival advantage with gilteritinib. Treated patients experienced a median 36 percent reduction in mortality compared to subjects in the chemotherapy-alone group (9.3 months vs. 5.6 months). The difference was even greater after 1 year, at 37.1 percent compared to 16.7 percent in the standard chemo group.
The combined rate of complete remission and complete remission with partial hematologic recovery—no evidence of disease and partial recovery of blood counts—was 34.0 percent with gilteritinib and 15.3 percent for patients in the chemotherapy arm.
“This survival data, combined with gilteritinib's relatively low toxicity, establishes gilteritinib monotherapy as the new standard of care for patients with relapsed or refractory FLT3-mutated AML,” said Alexander E. Perl, MD, Associate Professor of Hematology/Oncology at the Perelman School of Medicine and a member of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.
“The relatively low toxicity and the fact that gilteritinib is an oral therapy means physicians can manage patients in the outpatient setting, which is a paradigm shift for the treatment of this disease,” Perl told a press conference.
The randomized, phase III ADMIRAL trial was designed to determine whether gilteritinib treatment improved survival for patients with relapsed or refractory FLT3-mutated AML over standard chemotherapy regimens.
Among 371 patients enrolled in the study, 247 received gilteritinib while 124 were treated with standard chemotherapy.
At baseline, 88.4 percent of patients had FLT3-internal random duplications—mutations that carry increased risk of early relapse and poor survival. In addition, 8.4 percent had mutations in FLT3-tyrosine kinase domain, and 1.9 percent had both. Among patients, 39.4 percent had refractory AML and 60.6 percent had relapsed disease.
Patients refractory to induction chemotherapy or untreated after first relapse were randomized to continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomization selected chemotherapy regimen, including low-dose cytarabine in 14.7 percent; azacitidine in 22.9 percent; mitoxantrone etoposide and cytarabine in 25.7 percent; and 26 percent treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin.
Overall survival and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints were event-free survival (EFS) and CR rate; safety/tolerability was also examined. CR rates were 21.1 percent and 10.5 percent, and median EFS was 2.8 months and 0.7 months in the gilteritinib and standard chemotherapy arms, respectively.
Compared with salvage chemotherapy, gilteritinib was generally associated with lower toxicity during the first 30 days of treatment. Adjusted for exposure duration, serious treatment-emergent adverse events (AEs) per patient year were less common with gilteritinib (7.1%) than standard chemotherapy (9.2%).
Common AEs in all subjects included febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Grade 3 or greater adverse events in the treatment group were anemia in 19.5 percent, febrile neutropenia in 15.4 percent, thrombocytopenia in 12.2 percent, and decreased platelet counts in 22.2 percent.
Perl noted that about one in three AML patients in the U.S. harbor the FLT3 mutation, and those with RR-AML typically have a poor prognosis. Remission rates are low with standard chemotherapy and when remission is achieved it tends to be of short duration, he noted. Survival rates are short and many have a poor response to salvage therapy.
Among all AML patients, 40-70 percent relapse after achieving remission with induction chemotherapy, and up to 40 percent are refractory to induction chemotherapy and do not achieve complete remission.
“Adding this to frontline therapy may generate even better results. Clinical trials testing gilteritinib in combination with other therapies, and testing gilteritinib as frontline therapy for newly diagnosed patients, has already been launched,” he noted.
“The longest survival in the gilteritinib arm was seen in patients who proceeded to transplant and then resumed gilteritinib to prevent relapse. But, unfortunately, long-term survival was very uncommon on either treatment arm.”
Panel moderator Louis M. Weiner, MD, Director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., commented on the findings.
“This is a practice-changing strategy, something that has been needed in the field of acute myeloid leukemia for the entire time that I have been an oncologist,” he stated. “To have something like this is special and important.”
Kurt Samson is a contributing writer.