LAUSR

Introduction: Gilteritinib is a potent/selective oral inhibitor of FMS-like tyrosine kinase 3 (FLT3). Based upon interim analysis response rates from the ADMIRAL Phase III study of gilteritinib vs salvage chemotherapy (SC) in patients (pts) with R/R FLT3mut+ AML (NCT02421939), gilteritinib became the first FLT3 inhibitor approved as single agent therapy in this population. Here we present the final results of this pivotal trial. Methods: Adults with confirmed FLT3mut+ AML (FLT3-ITD and/or FLT3-TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomization selected SC: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA). Prior FLT3 inhibitor use, other than midostaurin or sorafenib, was excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints were event-free survival (EFS) and CR rate; safety/tolerability was also examined. Results: A total of 371 pts were randomized: 247 to gilteritinib and 124 to SC (MEC, 25.7%; FLAG-IDA, 36.7%; LoDAC, 14.7%; AZA, 22.9%). Median age was 62 years (range, 19-85). Baseline FLT3 mutations were: FLT3-ITD, 88.4%; FLT3-TKD, 8.4%; both FLT3-ITD and FLT3-TKD, 1.9%; unconfirmed, 1.3%. Overall, 39.4% of pts had refractory AML and 60.6% had relapsed AML. Patients randomized to gilteritinib had significantly longer OS (9.3 months) than SC (5.6 months; hazard ratio [HR] for death = 0.637; P=0.0007); 1-year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (P=0.0001); CR rates were 21.1% and 10.5% (2-sided P=0.0106). Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, P=0.0830). Common adverse events (AEs) in all randomized pts were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Adjusted for exposure duration, serious treatment-emergent AEs per patient year were less common with gilteritinib (7.1%) than SC (9.2%). Conclusions: In patients with R/R FLT3mut+ AML, the potent, selective FLT3 inhibitor gilteritinib resulted in significantly longer OS and higher response rates compared with chemotherapy and had a favorable safety profile. These results change the treatment paradigm for salvage therapy of R/R FLT3mut+ AML and establish gilteritinib as the new standard of care. Citation Format: Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, Maria R. Baer, Richard A. Larson, Celalettin Ustun, Francesco Fabbiano, Antonio Di Stasi, Robert Stuart, Rebecca Olin, Margaret Kasner, Fabio Ciceri, Wen-Chien Chou, Nikolai Podoltsev, Christian Recher, Hisayuki Yokoyama, Naoko Hosono, Sung-Soo Yoon, Je-Hwan Lee, Timothy Pardee, Amir T. Fathi, Chaofeng Liu, Xuan Liu, Erkut Bahceci, Mark J. Levis. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT184.