As reported in The New England Journal of Medicine by Alexander E. Perl, MD, of Abramson Cancer Center, University of Pennsylvania, and colleagues, the phase III ADMIRAL trial showed improved overall survival with the oral FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib vs salvage chemotherapy in patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML).¹ Gilteritinib was approved in this setting in November 2018 on the basis of an interim analysis of response rate and duration of response in the gilteritinib arm of the trial.

Alexander E. Perl, MD

Study Details

In the open-label trial, 371 patients from 107 sites in 14 countries enrolled between October 2015 and February 2018 were randomly assigned 2:1 to receive gilteritinib at 120 mg/d (n = 247) or investigator’s choice of salvage chemotherapy (n = 124), with treatments being given in 28-day cycles. Randomization was stratified by response to previous therapy and investigator-selected chemotherapy. Chemotherapy was chosen prior to randomization and could consist of mitoxantrone, etoposide, and cytarabine (MEC); fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA); low-dose cytarabine; or azacitidine. MEC and FLAG-IDA were considered high-intensity regimens. Patients receiving high-intensity chemotherapy regimens were assessed for response on or after day 15 to determine the need for a second induction cycle. Patients receiving gilteritinib or low-intensity chemotherapy continued treatment until lack of clinical benefit, unacceptable toxicity, or other protocol-specified reasons for treatment discontinuation. Crossover between groups was not permitted.

The two primary endpoints were overall survival and percentage of patients with complete remission who had full or partial hematologic recovery in the intention-to treat population. The current report presents the final analysis of the trial, with event cutoff in September 2018.

Among patients in the gilteritinib group, 60% relapsed after first-line therapy compared with 61% in the chemotherapy group. Approximately 40% of the gilteritinib group had primary refractory disease without HSCT after first-line therapy, compared with 39% in the chemotherapy group.

The FLT3 mutation subtype was internal tandem duplication alone in 87% of the gilteritinib group vs 91% of the chemotherapy group, tyrosine kinase domain alone in 9% vs 8%, and both in 3% vs 0%. The preselected salvage chemotherapy regimen was a high-intensity regimen in 60% of both groups.

Overall Survival and Complete Remission

Overall, 94% of patients receiving high-intensity chemotherapy received one treatment cycle. The median duration of low-intensity chemotherapy was 4 weeks. The median number of gilteritinib cycles was five. More patients in the gilteritinib group underwent HSCT during the study (26% vs 15%).

The median duration of follow-up for overall survival in the final analysis was 17.8 months. The median overall survival was 9.3 months in the gilteritinib group vs 5.6 months in the chemotherapy group (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.49–0.83, P < .001). The benefit of gilteritinib was maintained in analysis-censoring survival data at the time of HSCT (HR = 0.58, 95% CI = 0.43–0.76).

In subgroup analyses, hazard ratios were 0.72 (95% CI = 0.52–1.00) among 145 vs 75 white patients and 0.34 (95% CI = 0.20–0.60) among 69 vs 33 Asian patients; 0.62 (95% CI = 0.47–0.82) among those with internal tandem duplication mutation alone and 0.69 (95% CI = 0.29–1.64) among those with tyrosine kinase domain mutation alone; 0.66 (95% CI = 0.47–0.93) vs patients receiving high-intensity chemotherapy and 0.56 (95% CI = 0.38–0.84) vs those receiving a low-intensity regimen. By cytogenetic risk, hazard ratios were 0.60 (95% CI = 0.44–0.82) among patients with intermediate status, 1.63 (95% CI = 0.69–3.85) among those with unfavorable status, and 0.46 (95% CI = 0.25–0.84) among those with unknown risk status.

By response to first-line therapy, hazard ratios were 0.99 (95% CI = 0.63–1.55) among those with primary refractory disease without HSCT (median overall survival of 10.4 vs 6.9 months), 0.38 (95% CI = 0.20–0.75) in 31 vs 17 patients with relapse up to 6 months after allogeneic HSCT, 0.86 (95% CI = 0.26–2.80) among 17 vs 8 patients with relapse more than 6 months after allogeneic HSCT, 0.49 (95% CI = 0.30–0.80) among 67 vs 34 with relapse up to 6 months after composite complete remission and no HSCT, and 0.49 (95% CI = 0.25–0.98) among 34 vs 17 with relapse more than 6 months after composite complete remission and no HSCT.

Complete remission with full or partial hematologic recovery occurred in 34.0% vs 15.3% of patients (absolute 18.6% risk difference, 95% CI = 9.8%–27.4%), with complete remission and full recovery occurring in 21.1% vs 10.5% (absolute 10.6% risk difference, 95% CI = 2.8%–18.4%). The median duration of complete remission with full or partial hematologic recovery was 11.0 months in the gilteritinib group and could not be evaluated in the chemotherapy group due to censoring. The median event-free survival was 2.8 months vs 0.7 months (HR = 0.79, 95% CI = 0.58–1.09).

Adverse Events

The median duration of exposure to gilteritinib and chemotherapy was 18 weeks and 4 weeks, respectively. The incidence of exposure-adjusted grade ≥ 3 adverse events was 19.3 events per patient-year in the gilteritinib group and 42.4 events per patient-year in the chemotherapy group. The most common grade ≥ 3 adverse events in the gilteritinib group were febrile neutropenia (45.9% vs 36.7% in the chemotherapy group), anemia (40.7% vs 30.3%), and thrombocytopenia (22.8% vs 16.5%). The incidence of exposure-adjusted serious adverse events was 7.1 per patient-year in the gilteritinib group and 9.2 per patient-year in the chemotherapy group. The most common serious adverse events considered to be related to gilteritinib treatment were febrile neutropenia (9.3%), increased alanine transaminase levels (4.5%), and increased aspartate transaminase levels (4.1%).

Drug-related adverse events led to discontinuation of gilteritinib in 11.0% of patients. Fatal infection occurred in 11.4% and 6.4% of patients. The most common fatal adverse events considered to be drug-related in the gilteritinib group were pneumonia (1.2%), large intestine perforation (0.8%), and septic shock (0.8%).

The investigators concluded: “Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.” 

DISCLOSURE: The study was funded by Astellas Pharma. For full disclosures of the study authors, visit nejm.org. Dr. Perl has served as an advisor or consultant for Astellas, Daiichi Sankyo, Novartis, and Arog, and has received research funding from Astellas, Daiichi Sankyo, FujiFilm, and Novartis.

REFERENCE

1. Perl AE, Martinelli G, Cortes JE, et al: Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381:1728-1740, 2019.