NEW YORK – A University of Pennsylvania-led team has published details from a Phase III trial demonstrating that the FLT3 inhibitor gilteritinib (Astellas Pharma's Xospata) can significantly extend average survival in individuals with relapsed or refractory forms of acute myeloid leukemia (AML) containing FLT3 gene mutations.
"We found that in this population of patients, gilteritinib resulted in superior overall survival and percentages of remission as compared with salvage chemotherapy," first author Alexander Perl, a hematology and oncology researcher at UPenn's Perelman Center for Advanced Medicine, and his colleagues wrote.
For the trial, the researchers assessed overall survival and full or partial remission as co-primary endpoints in 371 patients with FLT3-mutated AML who were randomized to get gilteritinib or salvage chemo at a ratio of two-to-one, respectively. In the 247 patients receiving gilteritinib, they saw an average overall survival of 9.3 months compared to 5.6 months, on average, in the 124 FLT3-mutated AML patients treated with salvage chemotherapy.
Findings from the trial, known as ADMIRAL, were published online today in the New England Journal of Medicine, and presented at the American Association for Cancer Research annual meeting in Atlanta in April.
Last November, the US Food and Drug Administration approved gilteritinib for relapsed or treatment-refractory FLT3-mutated AML, in combination with Invivoscribe Technologies' LeukoStrat CDx companion diagnostic assay for identifying FLT3 mutations.
The team noted that gilteritinib targets in-frame internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations in FLT3, as well as drug resistance-related mutations in the tyrosine kinase gene AXL.
For the Astellas Pharma-sponsored trials, the researchers started with central lab, PCR-based screening for FLT3 mutations in 625 adult AML patients treated at 107 centers in more than a dozen countries between mid-October of 2015 and late February 2018.
That search that led to 366 FLT3-mutated cases, including 328 with FLT3-ITD mutations, 31 FLT3-TKD-mutated cases, and seven cases marked by both ITD and TKD mutations in FLT3. FLT3 mutations were unconfirmed in the remaining five patients randomized to the gilteritinib or salvage chemotherapy treatment arms. The researchers noted that most of those patients — nearly 61 percent — had relapsed forms of AML, while the remaining 39.4 percent of cases were classified as primary refractory. At the time of data cut off last fall, more than three-dozen individuals were continuing to receive gilteritinib.
"Our trial showed a survival advantage for FLT3-targeted therapy in patients with relapsed or refractory AML after data were censored for transplantation," the authors noted. "Although gilteritinib therapy resulted in 63 patients being able to undergo transplantation, the contribution of the transplantation to the survival benefit from gilteritinib is difficult to assess."
Along with that increase in overall survival, the gilteritinib-treated group came out ahead when it came to rates of complete remission with hematologic recovery, at 34 percent compared to 15.3 percent in the comparator arm, the team reported. Another 21.1 percent had complete remission without hematologic recovery after gilteritinib compared to 10.5 percent after the salvage chemo.
In the study, median overall survival and complete remission rates for patients on gilteritinib were similar regardless of their FLT3 mutation type.
Additionally, the researchers reported an average event-free survival time of 2.8 months after gilteritinib treatment in the FLT3-mutated AML group, but just 0.7 months for those in the group receiving salvage chemotherapy. They noted that serious, high-grade side effects were more common in those treated with chemo after adjusting for the time individuals spent on treatment, though some adverse events were described in gilteritinib recipients, including myelosuppression, febrile neutropenia, and anemia.