RATIFY
Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation
Phase 3N = 717NCT00651261
- Population
- Newly diagnosed AML with a FLT3 mutation, aged 18 to 59 years
- Design
- Randomized, double-blind, placebo-controlled phase 3 trial (CALGB 10603; the CALGB is now part of the Alliance for Clinical Trials in Oncology). 3277 patients were preregistered and screened for FLT3 mutations; 717 were randomized, stratified by FLT3 subtype (TKD; ITD with a high or low mutant-to-wild-type allelic ratio). Standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation plus midostaurin or placebo, then midostaurin or placebo maintenance for patients in remission. Allogeneic transplantation was allowed. Primary end point: overall survival. Event-free survival was defined as time from randomization to relapse, death from any cause, or failure to achieve protocol-specified complete remission. P values for the primary analyses of overall and event-free survival are one-sided, as the trial design specified.
- Primary endpoint
- OS
- Arms
- Midostaurin + chemotherapy (experimental, n = 360): Daunorubicin and cytarabine induction, high-dose cytarabine consolidation, plus midostaurin; midostaurin maintenance
- Placebo + chemotherapy (control, n = 357): Daunorubicin and cytarabine induction, high-dose cytarabine consolidation, plus placebo; placebo maintenance
- People
- Stone RM, Alliance for Clinical Trials in Oncology
OSHR 0.78 (95% CI 0.63–0.96)Δ median OS+49.1 monthsEFSHR 0.78 (95% CI 0.66–0.93)Δ median EFS+5.2 months
Show the numbers
| Endpoint | Analysis | Midostaurin + chemotherapy | Placebo + chemotherapy | Effect |
|---|---|---|---|---|
| OSRandomized patients (N = 717); the abstract does not use the term ITT | primaryStone 2017 | median 74.7 months | median 25.6 months (18.6–42.9) | HR 0.78 (95% CI 0.63–0.96)P=0.009 (one-sided)The 95% CI for the midostaurin median is 31.5 months to not reached, so it is not stored as an interval. The authors state that the difference in medians may be large because of inflection points on the Kaplan-Meier curves and that the hazard ratio reflects the benefit better. In the sensitivity analysis censoring patients at transplantation there was a 24.3% lower risk of death, but the difference was not significant (P=0.08 by log-rank test); overall survival did not differ significantly by trial regimen within each FLT3 subtype (the trial was not powered for subgroups). Median follow-up among the 359 survivors was 59 months. |
| EFSRandomized patients (N = 717); the abstract does not use the term ITTTime from randomization to relapse, death from any cause, or failure to achieve protocol-specified complete remission | primaryStone 2017 | median 8.2 months (5.4–10.7) | median 3 months (1.9–5.9) | HR 0.78 (95% CI 0.66–0.93)P=0.002 (one-sided)Many patients were classified as having an early event because they did not achieve protocol-specified complete remission (213, 29.7%, never achieved complete remission), as the full text states. |
| Endpoint | Analysis | Midostaurin + chemotherapy | Placebo + chemotherapy | Effect |
|---|---|---|---|---|
| OSRandomized patients (N = 717); the abstract does not use the term ITT | primaryStone 2017 | median 74.7 months | median 25.6 months (18.6–42.9) | HR 0.78 (95% CI 0.63–0.96)P=0.009 (one-sided)The 95% CI for the midostaurin median is 31.5 months to not reached, so it is not stored as an interval. The authors state that the difference in medians may be large because of inflection points on the Kaplan-Meier curves and that the hazard ratio reflects the benefit better. In the sensitivity analysis censoring patients at transplantation there was a 24.3% lower risk of death, but the difference was not significant (P=0.08 by log-rank test); overall survival did not differ significantly by trial regimen within each FLT3 subtype (the trial was not powered for subgroups). Median follow-up among the 359 survivors was 59 months. |
| EFSRandomized patients (N = 717); the abstract does not use the term ITTTime from randomization to relapse, death from any cause, or failure to achieve protocol-specified complete remission | primaryStone 2017 | median 8.2 months (5.4–10.7) | median 3 months (1.9–5.9) | HR 0.78 (95% CI 0.66–0.93)P=0.002 (one-sided)Many patients were classified as having an early event because they did not achieve protocol-specified complete remission (213, 29.7%, never achieved complete remission), as the full text states. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.78 | 0.63–0.96 |
| EFS | 0.78 | 0.66–0.93 |
- Midostaurin + chemotherapy (experimental)
- Placebo + chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Midostaurin + chemotherapy | Placebo + chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 47 | 64.7% | 28.0% |
| 93 | 42.2% | 8.1% |
| 140 | 27.3% | 2.3% |
| 187 | 17.6% | 0.6% |
- Midostaurin + chemotherapy (experimental)
- Placebo + chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Midostaurin + chemotherapy | Placebo + chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 5 | 65.5% | 31.5% |
| 10 | 42.9% | 9.9% |
| 15 | 28.1% | 3.1% |
| 21 | 16.9% | 0.8% |