Patients with FLT-3 mutated acute myeloid leukemia (AML) lived longer with the addition of midostaurin (PKC412) to standard chemotherapy, followed by 1 year of maintenance therapy, according to results from the CALGB 10603 study reported by Richard Stone, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. The patients were between 18 and 60 years old and had newly-diagnosed, untreated disease.
The improvement in overall survival (OS) and event-free survival (EFS) with midostaurin, in patients who did and did not have stem cell transplantation (SCT), along a positive safety profile, suggest this represents a new standard of care, according to Dr. Stone.
Midostaurin, a multi-targeted small molecule FLT3 inhibitor, is active against both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant FLT3 AML. About 25-30% of patients with AML have the ITD mutation, which is associated with a high rate of relapse and a poor prognosis, and about 5-10% have the TKD mutation that has an uncertain impact on prognosis.
A total of 887 of the 3,279 patients (27%) screened between May 2008 and October 2011 had the FLT3 mutation. Of these, 717 were randomized to midostaurin (n = 360) or placebo (n = 357) in this international, phase 3 trial. The mutation analysis was conducted at one of nine academic laboratories, with results provided within 48 hours. Up to 5 days of treatment with hydroxyurea was allowed while awaiting the results of the analysis.
Induction therapy consisted of oral midostaurin 50 mg twice daily or placebo on days 8 to 21, plus intravenous daunorubicin 60 mg/m2 on days 1 to 3 and cytarabine 200 mg/m2 on days 1 to 7. A second cycle was given depending on the results of the day 21 marrow. Consolidation therapy consisted of midostaurin 50 mg twice daily or placebo on days 8 to 21 and cytarabine 3 mg/m2 on days 1, 3, and 5. Maintenance therapy consisted of midostaurin 50 mg twice daily or placebo on days 1 to 28 for 12 cycles. Of note, the primary analysis of the primary endpoint of OS, not censored for SCT, occurred early, after the protocol was revised because of a lower rate of deaths and a higher rate of SCT (57% overall, 25% after first complete remission) than expected. Further, more patients had a TKD mutation, which is associated with better survival. The median follow-up was 56.7 months for survivors.
The rate of death was similar in the groups (18 with midostaurin and 19 with placebo). More midostaurin-treated patients had a complete response by day 60 (59%, vs 53% with placebo; p = 0.15), and the median time to complete response was 35 days in both groups. Combining the induction and consolidation periods, there was a significantly greater complete response rate with midostaurin at 66% versus 59% with placebo (p = 0.045), with the median time of 37 days and 36 days, respectively.
Treatment with midostaurin reduced the risk of death by 23%, and the primary endpoint of overall survival was significantly improved (Figure 1). The median OS was 74.7 months and 25.6 months in the midostaurin and placebo groups. Midostaurin-treated patients who had SCT had a somewhat higher 4-year survival of 63.8% compared against 55.7% with placebo. This effect was further enhanced in patients who had SCT after the first complete remission, with midostaurin-treated patients having a 39% improvement in OS compared with placebo.
With midostaurin compared with placebo, there was a significantly longer EFS (median 8 months vs. 3 months; p = 0.0025) and higher rate of EFS (27.6% vs. 20.2%). When combining the induction and consolidation periods were combined, EFS was 27% greater with midostaurin than placebo, with a median EFS of 11.3 months and 6.1 months, respectively (p = 0.0002). EFS was improved regardless of the mutation subtype.
Disease-free survival was significantly prolonged with midostaurin at 25.9 months compared with 14.4 months with placebo (p = 0.002), and a 4-year disease-free survival rate of 46.4% and 37.4%, respectively.
The results of CALGB 10603 suggest a new standard of care for patients with FLT-3 AML that includes midostaurin along with conventional treatment, according to the investigators. Further, it supports the feasibility of a large-scale study of AML using genotyping at the time of disease diagnosis and conducted by an international academic collaboration.
Source: ASH 2015,