Gilteritinib improves survival in relapsed or refractory AML
Gilteritinib, a novel inhibitor of the tyrosine kinase FLT3, improves survival outcomes among patients with relapsed or refractory acute myeloid leukaemia (AML) with FLT3 mutations vs standard chemotherapy, according to results of the phase III ADMIRAL trial reported at the American Association for Cancer Research (AACR) Annual Meeting 2019 held in Atlanta, Georgia, US.
The study, where 371 patients (median age, 62 years) were recruited, showed that those who were randomized to receive gilteritinib (n=247) had significantly longer overall survival (OS; median, 9.3 months vs 5.6 months; hazard ratio [HR], 0.637; p=0.0007) than those who received standard chemotherapy (n=124). This data translates to a 36 percent reduction in risk of death for those who received gilteritinib compared with those who received standard chemotherapy. [Perl AE, et al, AACR 2019, abstract CT184]
Overall, 39.4 percent of the patients had refractory AML and 60.6 percent had relapsed AML. Baseline FLT3 mutations were FLT3 internal tandem duplication (ITD) mutations (88.4 percent), FLT3 tyrosine kinase domain (TKD) mutations (8.4 percent), and both FLT3-ITD and FLT3-TKD mutations (1.9 percent).
After 12 months of follow-up, the survival rate was higher in the gilteritinib arm vs the standard chemotherapy arm (37.1 percent vs 16.7 percent).
Rates of complete remission (CR) and CR with partial recovery of blood cells (CRh) were also higher among those who received gilteritinib vs standard chemotherapy (34 percent vs 15.3 percent; p=0.0001).
Moreover, there was a trend towards longer median event-free survival among those who received gilteritinib vs standard chemotherapy (2.8 months vs 0.7 months; HR, 0.793; p=0.083).
“The final results of the ADMIRAL trial showed that gilteritinib is superior to standard chemotherapy, as measured by improved OS. This data, combined with gilteritinib’s relatively low toxicity, establish gilteritinib monotherapy as a new standard of care for patients with relapsed or refractory FLT3-mutated AML,” commented lead investigator Dr Alexander Perl from the Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, US.
Common grade ≥3 adverse events (AEs) related to gilteritinib included anaemia (19.5 percent), febrile neutropenia (15.4 percent), and thrombocytopenia (12.2 percent). Serious treatment-emergent AEs per patient per year were less common in the gilteritinib group vs standard chemotherapy group (7.1 percent vs 9.2 percent).
“The longest survival in the gilteritinib arm was seen among patients who proceeded to transplant and then resumed gilteritinib to prevent relapse. Unfortunately, long-term survival was still uncommon in either treatment arm,” Perl said.
“To improve long-term outcomes, clinical trials testing gilteritinib with other therapies for relapsed or refractory FLT3-mutated AML and testing gilteritinib as frontline therapy for newly diagnosed patients have already been launched,” he added.
Patients in the gilteritinib arm of the ADMIRAL trial received continuous 28-day cycles of gilteritinib 120 mg per day or pre-randomization selected chemotherapy, including low-dose cytarabine, azacytidine, mitoxantrone/etoposide/cytarabine, or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin.
In November 2018, the US FDA approved gilteritinib for the treatment of adult patients with relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test. [https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-adult-patients-who-have-relapsed-or-refractory-acute-myeloid-leukemia-aml]
The US FDA also approved the LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic test for the detection of FLT3 mutation in patients with AML.
FLT3 is one of the most frequently mutated genes in AML. Activating mutations in FLT3 are present in approximately 25−30 percent of newly diagnosed AML cases. Patients with AML harbouring the FLT3 ITD mutations have poorer prognosis following chemotherapy. [Blood 2016;128:2830]