Final results from the phase 3 randomized, open-label ADMIRAL trial (ClinicalTrials.gov Identifier: NCT02421939) showed significantly improved overall survival (OS) for patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia (R/R AML) who received gilteritinib, an oral FLT3 inhibitor, compared with salvage chemotherapy (P =.0007).1
Patients with AML who experience disease relapse following treatment with first-line chemotherapy or do not respond to such treatment have a poor prognosis. Furthermore, FLT3-mutated disease, occurring in 25% to 30% of patients with AML, is considered to be particularly aggressive.2
In November 2018, gilteritinib was approved by the US Food and Drug Administration (FDA) for the treatment of patients with FLT3 mutation-positive AML on the basis of interim results from the ADMIRAL trial.3 Final results of the study were presented at the American Association for Cancer Research (AACR) Annual Meeting 2019.1
Inclusion criteria for the ADMIRAL trial included disease that was FLT3-mutation positive, defined as disease characterized by a FLT3 internal tandem duplication or specific mutations in the tyrosine kinase domain of FLT3, and disease that either did not respond to or relapsed following first-line chemotherapy. The coprimary end points of the study were OS and the combined rate of complete remission (CR) and CR with partial hematological recovery (CR/CRh). Secondary end points included safety/tolerability.
Of the 371 patients enrolled in the study, 247 received gilteritinib and 124 received investigators’/patients’ choice of salvage chemotherapy (ie, low-dose cytarabine; azacitidine; mitoxantrone/etoposide/cytarabine; and granulocyte colony-stimulating factor, fludarabine/cytarabine/idarubicin), and stratified by prior response to chemotherapy and the intensity of the salvage chemotherapy.
Median OS was 9.3 months and 5.6 months for patients receiving gilteritinib and salvage chemotherapy, respectively (hazard ratio [HR], 0.637; P =.0007). A comparison of the 2 study arms also showed significantly different CR/CRh rates in favor of gilteritinib (34.0% vs 15.3%; P =.0001).
Common grade 3 or higher adverse events for patients in the gilteritinib arm included anemia (19.5%), febrile neutropenia (15.4%), and thrombocytopenia (12.2%). Of note, serious, treatment-emergent adverse events that were adjusted for exposure duration occurred in 7.1% and 9.2% of patients receiving gilteritinib and salvage chemotherapy, respectively.
“These results change the treatment paradigm for salvage therapy of relapsed/refractory FLT3 mutation-positive AML and establish gilteritinib as the new standard of care,” the study authors wrote.1
In commenting on this study, Ross Levine, MD of Memorial Sloan Kettering Cancer Center in New York, NY concurred that these results, along with the FDA approval of gilteritinib, “establish this as the treatment of choice for FLT3-mutant AML in the relapsed/refractory setting.”2 However, he cautioned that single-agent gilteritinib is not a cure for AML, and that further investigations of gilteritinib in combination with other targeted agents are needed.2
- PerlAE, MartinelliG, CortesJE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the phase III ADMIRAL trial. Presented at: the American Association for Cancer Research (AACR) Annual Meeting 2019; March 31-April 3, 2019; Atlanta, GA. Abstract CT184.
- Gilteritinib likely new standard care for AML [published online April 1, 2019]. Cancer Discov. doi: 10.1158/2159-8290.CD-NB2019-046
- Gilteritinib (Xospata®) [package insert]. Northbrook, Illinois: Astellas Pharma US, Inc.; 2018.