Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.
The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.
Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.
Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.
Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.
In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.
FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.
The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).
Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).
Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).
Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.
Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.
At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.
Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.
Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.
“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”
Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.