February 4, 2021 - The China National Medical Products Administration has granted a conditional approval to gilteritinib for use in adult patients with relapsed or refractory acute myeloid leukemia with a FLT3 mutation detected by a validated test.
The China National Medical Products Administration (NMPA) has granted a conditional approval to gilteritinib (Xospata) for use in adult patients with relapsed or refractory acute myeloid leukemia with a FLT3 mutation detected by a validated test.1
The regulatory decision was based on data from the phase 3 ADMIRAL trial (NCT02421939), which showed that gilteritinib significantly prolonged overall survival (OS) compared with salvage chemotherapy in this patient population.2 The median OS with the FLT3 inhibitor was 9.3 months versus 5.6 months with (HR, 0.64; 95% CI, 0.49-0.83; P = .0004); this translated to a 36% reduction in the risk of death. The NMPA also reviewed pharmacokinetics data from Chinese patients enrolled to the ongoing phase 3 COMMODORE trial (NCT03182244).
“Patients with relapsed or refractory AML with a FLT3 mutation are in urgent need of new treatment options,” Professor Ma Ju, director of the Harbin Institute of Hematology, China, stated in a press release. “As the first approved targeted therapy agent to treat relapsed or refractory AML with a FLT3 mutation in China, gilteritinib, which was approved under an expedited pathway, has enabled patients in China to have rapid access to a novel treatment option.”
In the international phase 3 ADMIRAL trial, a total of 371 patients with FLT3-mutated relapsed/refractory AML were randomized in a 2:1 fashion to either gilteritinib, given at a daily dose of 120 mg (n = 247), or salvage chemotherapy (n = 124). The regimens used in the control arm included mitoxantrone, etoposide, plus cytarabine; fludarabine, cytarabine, idarubicin and granulocyte colony-stimulating factor; low-dose cytarabine; and azacitidine.
Following treatment, all participants underwent hematopoietic stem cell transplantation (HSCT). Those in the investigational arm went on to continue treatment. Notably, crossover from the placebo arm to the investigational arm was not allowed.
To be eligible for participation, patients needed to have AML that harbored a FLT3-ITD or FLT3-TKD mutation, a mean of triplicate Friderica-correct QT interval of less than 450 milliseconds at screening per central reading, and they needed to be refractory to induction chemotherapy or in untreated first relapse.
The median age of participants was 62 years, and 54% were female. Seventy-three percent of patients had intermediate-risk cytogenetics, 88% had tumors that harbored FLT3-ITD mutations, 20% had undergone prior HSCT and 82% had received up-front intensive chemotherapy. Moreover, 39% of participants had primary refractory disease without HSCT, while 27% relapsed 6 months or less following composite complete remission (CRc).
The co-primary end points of ADMIRAL were OS and CR/CRh, while key secondary end points include event-free survival (EFS), CR rate, leukemia-free survival, duration of remission, CRc rate, transplantation rate, brief fatigue inventory, CRh rate, transfusion conversion rate, and transfusion maintenance rate.
Additional results showed that the median EFS with gilteritinib was 2.8 months versus 0.7 months with chemotherapy (HR, 0.79; 95% CI, 0.58-1.09). Moreover, 34.0% of patients in the investigative arm achieved a CR with full or partial hematologic recovery versus 15.3% of those in the control arm, translating to a risk difference of 18.6 percentage points (95% CI, 9.8-27.4).A CR was achieved in 21.1% of patients who were given gilteritinib versus 10.5% of those who received chemotherapy, translating to a risk difference of 10.6 percentage points (95% CI, 2.8-18.4).
The safety of gilteritinib was examined in a total of 319 patients with relapsed/refractory AML who had been given at least 1 dose of gilteritinib at 120 mg. The most commonly experienced toxicities included increased alanine aminotransferase (ALT; 25.4%), increased aspartate aminotransferase (AST; 24.5%), anemia (20.1%), thrombocytopenia (13.5%), febrile neutropenia (12.5%), decreased platelet count (12.2%), and diarrhea (12.2%). Nausea (11.3%), increased blood alkaline phosphate (11%), fatigue (10.3%), decreased white blood cell count (10%), and increased blood creatine phosphokinase (10%), were also reported.
Among those who received the FLT3 inhibitor, 1 fatal adverse reaction of differentiation syndrome. The most frequently reported serious adverse effects in those who received the agent included febrile neutropenia (7.5%), increased ALT (3.4%), and increased AST (3.1%).
In the open-label, multicenter, randomized, phase 3 COMMODORE trial, investigators are again examining the safety and efficacy of gilteritinib compared with salvage chemotherapy in adult Chinese patients with relapsed/refractory AML, as well as those in other countries.3 The primary objective of this research is OS, while secondary end points will look at EFS, CR, and safety.
Previously, in November 2018, the FDA approved gilteritinib for use in adult patients with FLT3 mutation–positive, relapsed/refractory AML based on data from ADMIRAL.