Selective FLT3 inhibition promising in relapsed, refractory AML
medwireNews: The highly selective fms-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib elicits clinical responses and is well tolerated in patients with relapsed or refractory acute myeloid leukemia (AML), show phase I/II trial data.
In this first-in-human study, 252 adults who were either refractory to induction therapy or had relapsed after achieving remission with prior therapy were given oral gilteritinib once a day at one of seven doses ranging from 20 mg to 450 mg.
A clinical response, lasting for a median of 17 weeks, was achieved by 40% of 249 evaluable participants, with 8% achieving complete remission, 4% complete remission with incomplete platelet recovery, 18% complete remission with incomplete hematologic recovery, and 10% partial remission.
Of note, participants harboring FLT3 mutations – such as internal tandem duplications, point mutations in the D835 codon, or both – were more likely to respond than those with wild-type FLT3, with overall responses in 49% of 191 patients and 12% of 58, respectively.
Given that these mutations are a frequent mechanism of resistance to other FLT3 inhibitors, this finding “underscores the specificity of gilteritinib in targeting mutated FLT3,” the researchers say.
They note that gilteritinib was well tolerated, with a “modest” adverse event profile that could be managed in the outpatient setting.
The most common grade 3 or 4 toxicities were febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia, observed in 39%, 24%, 13%, 11%, and 11% of participants, respectively.
Febrile neutropenia, sepsis, and pneumonia were also among the most frequent serious adverse events occurring in at least 5% of patients, as were progressive disease, acute renal failure, pyrexia, bacteremia, and respiratory failure.
Ten percent of study participants required a dose reduction and an identical proportion discontinued gilteritinib due to treatment-emergent side effects. Of the 95 deaths that occurred during the course of the study, seven were considered possibly or probably related to treatment.
There were two dose-limiting toxicities in the 450 mg cohort, one case each of grade 3 diarrhea and elevated aspartate aminotransferase; thus, the 300 mg/day dose was established as the maximum tolerated dose.
And “[t]he 120 mg/day dose was chosen as the starting dose for future studies because it provides potent FLT3 inhibition and allows for dose modification without compromising tolerability or antileukaemic effects,” say Mark Levis, from Johns Hopkins University in Baltimore, Maryland, USA, and colleagues.
They conclude in The Lancet Oncology: “These data validate FLT3 as a high-value therapeutic target in acute myeloid leukaemia and lay the foundation for phase 3 studies comparing gilteritinib with standard chemotherapy or other targeted agents.”
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