The global, randomized, placebo-controlled phase 3 RATIFY trial demonstrated that midostaurin—an oral, multitargeted, small-molecule FLT3 inhibitor—when added to induction and consolidation chemotherapy followed by maintenance, led to a statistically significant overall survival benefit compared with standard chemotherapy in 3277 patients with acute myeloid leukemia (AML) and activating FLT3 mutations. The current post-hoc analysis of the RATIFY trial conducts a detailed comparison of the cumulative incidence of relapse (CIR) to assess whether the addition of midostaurin significantly lowered the risk for relapse.
In the RATIFY study, 717 patients were randomized to receive either midostaurin (50 mg orally twice daily on days 8-22) or placebo in combination with induction therapy, which consisted of daunorubicin (60 mg/m2 intravenously, days 1-3) and cytarabine (200 mg/m2, days 1-7), continuous intravenous infusion, plus midostaurin or placebo. Only patients achieving complete remission (CR) were allowed to receive consolidation therapy, consisting of 4 cycles of cytarabine 3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 plus midostaurin or placebo (50 mg orally twice daily, days 8-22) followed by twelve 28-day cycles of maintenance therapy with midostaurin or placebo (50 mg orally twice daily). A total of 409 patients underwent allogeneic stem-cell transplantation. CIR analyses were performed for 2 definitions of CR: CR per protocol (CR60; by day 60) and CR during induction (CRind; before protocol consolidation). CIR analyses treated relapses and AML deaths as events; deaths from other causes as competing risks; and survivors in CR as censored.
The efficacy analysis showed that a total of 403 patients achieved CR60, of which 212 were in the midostaurin arm versus 191 in the placebo arm (59% vs 53%; P = .15), and 441 patients achieved CRind (234 [65%] vs 207 [58%]; P = .053). In both subsets, if transplant patients were still included in the risk set, midostaurin had a lower CIR versus placebo (CR60: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.58-1.03], stratG P = .08; CRind: HR, 0.72 [95% CI, 0.55-0.94], stratG P = .02). However, there was no meaningful difference when stem-cell transplantation was included as a competing risk in sensitivity analyses (CR60: HR, 0.87 [95% CI, 0.63-1.19], stratG P = .34; CRind: HR, 0.81 [95% CI, 0.60-1.10], stratG P = .18). Of the patients who achieved CR60 (n = 148) or CRind (n = 154) and underwent transplant in first remission, CRind patients who received midostaurin were less likely to relapse (CR60: HR, 0.62 [95% CI, 0.33-1.14], stratG P = .12; CRind: HR, 0.47 [95% CI, 0.26-0.87], stratG P = .02).
The results of the post-hoc analysis of the RATIFY trial suggest that midostaurin decreases the risk for relapse in patients with FLT3 mutation‒positive, newly diagnosed AML, if transplantation is ignored.
Stone RM, et al. 2017 ASH. Abstract 2580.
