FDA Approves Rydapt for AML

The Food and Drug Administration has approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed FLT3-positive acute myeloid leukemia (AML) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

The drug has also been approved for the treatment of patients with advanced systemic mastocytosis (SM), including aggressive systemic mastocytosis (ASM), SM with associated hematological neoplasm (SM-AHN) and mast cell leukemia.

Rydapt was approved along with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, to test for FLT3 mutations in patients with AML.

The approval is based on the phase 3 RATIFY trial in AML and two single-arm, open-label studies of patients with SM. In the RATIFY trial, the addition of Rydapt to standard chemotherapy reduced the risk of death by 23 percent compared with chemotherapy alone in patients with AML who had an FLT3 mutation. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with Rydapt remained steady at 25 percent.

In the pivotal phase 2 trial considered for the SM approvals, among patients receiving six cycles of Rydapt, the rates of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria were 38 percent for ASM and 16 percent for SM-AHN. One patient with mast cell leukemia had a CR.

In the phase 3 RATIFY trial, 717 patients with newly diagnosed FLT3-mutant AML were randomized to standard induction and consolidation chemotherapy plus Rydapt (360 patients) or placebo (357 patients). Hydroxyurea was allowed for up to five days prior to beginning therapy, while FLT3 test results were obtained.

The median age in both treatment arms was 48 years, and there were more men in the Rydapt arm versus placebo. The primary endpoint of the study was OS, with secondary outcome measures such as event-free survival (EFS) and safety.

In uncensored data, median OS was 74.7 months with Rydapt versus 25.6 months with chemotherapy alone. The 5-year OS rate for patients in the Rydapt arm was 50.9 percent versus 43.9 percent with placebo. Median EFS in the Rydapt arm was 8.2 versus 3 months with placebo. The 5-year EFS rate with Rydapt was 27.5 percent versus 19.3 percent with placebo.

Median OS seen in the Rydapt arm was well beyond the researchers’ expectations of 20.9 months. A possible explanation for this could be the rates of stem cell transplantation or incomplete data.

Overall, 57 percent of patients received an allogeneic stem cell transplant at any time during the trial, more commonly in the Rydapt arm versus placebo (58 percent versus 54 percent). Median time to transplant was 5 months with Rydapt and 4.5 months with placebo. Twenty-five percent of transplants occurred during the first complete remission. Overall, 59 percent of patients in the Rydapt arm and 54 percent in the placebo group experienced a complete remission.

Median OS data were not obtained in the censored population. Overall, the 4-year censored OS rate with Rydapt was 63.8 percent versus 55.7 percent for placebo. In those censored for transplant, median EFS with Rydapt was 8.2 versus 3 months with placebo.

Grade 3 or higher adverse events (AEs) were similar between the Rydapt and placebo arms. Overall, 37 grade 5 AEs occurred in the study, which were similar between the two arms, at 5.3 percent with Rydapt versus 5 percent with placebo. A statistically significant difference was not observed for treatment-related grade 5 AEs.

In the phase 2 study of SM patients, the most common all-grade AEs included nausea, vomiting, diarrhea, swelling, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, fever, headache and difficulty breathing.