Treatment with gilteritinib (Xospata) improved survival and increased remission rates, compared with salvage chemotherapy, among patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), according to phase III trial findings.
Median overall survival (OS) among those treated with gilteritinib, a new, highly selective, oral FLT3 inhibitor, was significantly longer compared with patients treated with chemotherapy (9.3 months vs. 5.6 months; hazard ratio [ HR], 0.64; 95% CI, 0.49-0.83; P < .001). The percentages of patients who were alive at 1 year were 37.1% in the gilteritinib group and 16.7% in the chemotherapy group.
Of note, this significant improvement in OS associated with gilteritinib versus chemotherapy was seen across multiple subgroups, including the high-intensity and low-intensity chemotherapy cohorts and the high FLT3 internal tandem duplication allelic ratio subgroup (median OS, 7.1 vs. 4.3 months; HR, 0.49; 95% CI, 0.34-0.71).
Among patients with primary refractory AML, the median OS was 10.4 months in the gilteritinib arm and 6.9 months in the chemotherapy arm (HR, 0.99; 95% CI, 0.63-1.55).
Moreover, median event-free survival (EFS) was 2.8 months in the gilteritinib group, compared with 0.7 months in the chemotherapy group (HR, 0.79; 95% CI, 0.58-1.09). Thirty-four percent of patients in the gilteritinib group had complete remission with full or partial hematologic recovery, compared with 15.3% in the chemotherapy group (95% CI, 9.8-27.4), while complete remission rates were 21.1% and 10.5%, respectively (95% CI, 2.8-18.4).
Among patients in the FLT3 internal tandem duplication subgroup who had been randomly assigned to the gilteritinib group, 20.5% had a complete remission, compared with 9.7% in the chemotherapy group.
Grade 3 or higher adverse events (AEs) occurred less frequently in the gilteritinib group than in the chemotherapy group, with the most common associated with gilteritinib group being febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).
At the time of analysis, 110 patients were alive and 38 were continuing therapy with gilteritinib. Treatment discontinuation of gilteritinib occurred due to relapse, progression, or lack of efficacy (50.2%), death (14.6%), and AEs (11.3%).
“Patients with acute myeloid leukemia whose disease is refractory to, or relapses after, induction chemotherapy have a dismal prognosis with standard chemotherapy,” the researchers wrote. “…In patients with AML, the presence of the FLT3 (internal tandem duplications) mutation adversely affects survival, both at diagnosis and on failure of the initial therapy.”
Given positive results from a phase I/II study, the researchers conducted a multicenter, randomized phase III trial comparing gilteritinib with conventional salvage chemotherapy regimens to evaluate the clinical benefit of the agent at a starting dose of 120 mg per day.
Of 371 patients with relapsed or refractory FLT3-mutated AML, 247 were randomly assigned 2:1 to the gilteritinib group and 124 to the salvage chemotherapy group.
OS and the percentage of patients who had complete remission with full or partial hematologic recovery served as the primary endpoints. Secondary end points included EFS and the percentage of patients who had complete remission.
Overall, 60.6% of the patients had relapsed AML and 39.4% had primary refractory disease.
“Treatment options for patients with relapsed or refractory FLT3-mutated AML are largely limited to various salvage chemotherapy regimens, and there is no consensus regarding an approach. We found that in this population of patients, gilteritinib resulted in superior overall survival and percentages of remission as compared with salvage chemotherapy,” the researchers wrote, adding that a small signal regarding hepatic toxic effects warrants further study.
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019; 381:1728-1740. doi:10.1056/NEJMoa1902688.