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CALGB 10603/RATIFY 10-year follow-up: Midostaurin vs placebo plus intensive chemotherapy in newly diagnosed FLT3-mutated AML
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Data from the phase III C10603/RATIFY study (NCT00651261) demonstrated the benefit of adding the FLT3 inhibitor midostaurin to intensive chemotherapy in previously untreated adult patients with FLT3-mutated AML, with the combination resulting in superior EFS and OS vs placebo and leading to the approval of midostaurin combination therapy. Stone presented a 10-year follow-up from the C10603/RATIFY trial (NCT00651261) at the 66th ASH Annual Meeting and Exposition, reporting long-term EFS and OS data to determine the persistence of midostaurin benefit and to assess toxicity and relapse profiles.1 Patients (N = 717; midostaurin, n = 360; placebo, n = 357) were stratified according to FLT3 mutation status: ITD allelic ratio <0.7 vs ITD allelic ratio ≥0.7 vs TKD.1 |
| Key learnings |
| The improvement in median EFS with midostaurin was maintained, at 8.2 months (95% CI, 5.5–11.4) vs 3.0 months with placebo (95% CI, 1.9–6.0) (HR, 0.79; 95% CI, 0.67–0.94; p = 0.0067). |
| The estimated 10-year OS was 43.7% with midostaurin (95% CI, 38.7–49.3) vs 38.6% with placebo (95% CI, 33.6–44.4; p= 0.0485), with favorable OS trends across all three mutational subgroups. Stratification by gender revealed this 10-year OS benefit to be maintained in males (p = 0.005) but not females (p = 0.9), although EFS benefit was observed in both. |
| Transplantation in CR1 was highly beneficial overall, with a 10-year OS of 56.0% vs 35.8% without transplantation (p < 0.001). In patients in CR1 randomized to maintenance therapy, midostaurin reduced the CIR in patients with ELN 2017 favorable- and intermediate-risk, but not adverse-risk disease (HR, 0.71, 0.47, and 1.01, respectively). |
| The EFS benefit of midostaurin was maintained over time, whilst the OS benefit diminished, possibly partly attributable to aging patients. Patient and disease factors differed in early vs late relapse, suggesting potential benefit for alternative treatments based on therapy stage. |
Abbreviations: AE, adverse event; AML, acute myeloid leukemia; ASH, American Society of Hematology; CI, confidence interval; CIR, cumulative incidence of relapse; CR1, first complete remission; EFS, event-free survival; ELN, European LeukemiaNet; HR, hazard ratio; ITD, internal tandem duplication; OS, overall survival; TKD, tandem kinase domain.
References
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