In a phase III trial (Cancer and Leukemia Group B 10603 [RATIFY]/Alliance) reported in The New England Journal of Medicine, Stone et al found that the addition of midostaurin (Rydapt) to standard chemotherapy improved overall survival in patients with newly diagnosed acute myeloid leukemia (AML) with FLT3 mutation. The trial supported the recent approval of midostaurin in this setting. Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3-mutant and wild-type kinases.
In the double-blind trial, 717 patients aged 18 to 59 years from 275 sites in 17 countries were randomized between May 2008 and October 2011 to receive standard induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine plus midostaurin (n = 360) or placebo (n = 357). Midostaurin (and matching placebo) was given at 50 mg twice daily on days 8 to 21 of 28-day induction and, in patients achieving complete remission, consolidation cycles. Patients in remission after consolidation received maintenance midostaurin (or placebo) at 50 mg twice daily for 12 28-day cycles. Randomization was stratified by subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with high ratio (> 0.7) or a low ratio (0.05–0.7) of mutant to wild-type alleles. Allogeneic transplantation was permitted. The primary endpoint was overall survival.
Overall, FLT3 subtype was ITD-high in 214 patients, ITD-low in 341, and TKD in 162. The treatment groups were balanced for age, race, FLT3 subtype, cytogenetic risk, and blood cell counts; the placebo group had a higher proportion of women (59.4% vs 51.7%, P = .04).
Overall Survival and Adverse Events
Data for the current analysis were locked in March 2016. Median follow-up was 59 months in surviving patients. Median overall survival was 74.7 months in the midostaurin group vs 25.6 months in the placebo group (hazard ratio [HR] = 0.78, P = .009). Four-year overall survival was 51.4% vs 44.3%.
Subgroup analysis showed that hazard ratios favored midostaurin across FLT3 subtypes. Median event-free survival was 8.2 months vs 3.0 months (HR = 0.78, P = .002). Transplantation was performed in 57% of patients. In an analysis censoring patients at the time of transplantation, the risk of death was reduced by 24% in the midostaurin group, with benefit observed across FLT3 subtypes.
The rate of severe adverse events was similar in the two groups. Differences included a higher rate of grade ≥ 3 anemia (92.7% vs 87.8%, P = .03) and rash (14.1% vs 7.6%, P = .008) in the midostaurin group and more nausea (9.6% vs 5.6%, P = .05) in the placebo group.
The investigators concluded: “The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with [acute myeloid leukemia] and a FLT3 mutation.”
The study was funded by the National Cancer Institute and Novartis.
Stone RM, et al: N Engl J Med 377:454-464, 2017.