Radius: Midostaurin (mido) Plus Standard of Care (SOC) after Allogeneic Stem Cell Transplant (alloSCT) in Patients (pts) with FLT3-Internal Tandem Duplication (ITD)–Mutated Acute Myeloid Leukemia (AML)

Introduction Allogeneic stem cell transplant (alloSCT) provides pts with FLT3-ITD+ AML the highest likelihood of sustained remission, but relapse rates remain high. Post-SCT maintenance therapy may improve this outcome. Objective RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) investigated whether SOC ± mido after alloSCT reduced relapse rates in pts with FLT3-ITD+ AML. Methods Eligible adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (hematologic recovery and transfusion independence) were enrolled after engraftment and randomized 28 to 60 days after alloSCT to receive SOC ± mido 50 mg twice daily for up to 12 (4-week) cycles. The primary endpoint was relapse-free survival (RFS) at 18 mo after alloSCT; safety, pharmacokinetics (PK), in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay, overall survival (OS), and RFS at 24 mo after alloSCT were also assessed. The study was not adequately powered to detect a statistical difference between arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power if the incidence of relapse in the SOC + mido arm was 15%. Results 60 pts were randomized (30 per arm); 30 completed 12 cycles of therapy (14 with SOC; 16 with SOC + mido). The median dose intensity was 93 mg/day (range, 15-100 mg/day). Early discontinuations were similar between arms (15 with SOC; 13 with SOC + mido), often due to adverse events (AEs; 3% vs 27%) and consent withdrawal (20% vs 7%). 19 pts (63%) had mido dose modifications (84% due to AEs; concomitant CYP3A4 inhibitor, n = 1). With SOC alone, the estimated RFS (95% CI) at 18 mo was 76% (54%-88%) vs 89% (69%-96%) with SOC + mido (HR, 0.46 [95% CI, 0.12-1.86]; P = .27); the predicted relative reduction in the risk of relapse with the addition of mido was 54%. At 24 mo, OS (95% CI) was 85% with addition of mido (65%-94%) vs 76% with SOC alone (54%-89%) (P = .3418). PIA was evaluable in 28 pts in each arm; PK was evaluated in the SOC + mido arm. There was wide interpatient variability in trough levels of mido and its active metabolites ([CGP62221] + [CGP52421/5.4]) and in the degree of FLT3 inhibition. With mido, phosphorylated FLT3 (pFLT3) levels were With SOC and SOC + mido, AEs occurred in 87% and 100% of pts; serious AEs occurred in 57% and 30% of pts, respectively. 12 pts died on study (during follow-up phase; 8 with SOC and 4 with SOC + mido [n = 4 vs n = 2 due to AML disease progression]). Conclusion Mido as maintenance therapy was safely added for ≤ 1 y after alloSCT and, when added to SOC, reduced the predicted risk of relapse at 18 mo after alloSCT by 54% (vs SOC). Correlative analysis suggests that high levels of pFLT3 inhibition may positively influence outcomes.