Midostaurin (1) – Rydapt®

• Clinical trials
  • The benefit assessment was based on the double-blind, randomised, multicentre Phase III RATIFY trial (CPKC412A2301).
  • The trial was conducted with patients who had newly diagnosed FLT3-positive acute myeloid leukaemia (AML) and were aged between 18 and 60.
• Clinical trials
  • To address the question regarding the extent of the additional benefit of midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasia (SM-AHN) or mast cell leukaemia (MCL), the results of the registration-supporting studies CPKC412D2201 (pivotal) and CPKC412A2213 (supportive) are available.
  • These studies are single-arm, open-label, multicentre Phase II trials.

a) Adults with newly diagnosed acute myeloid leukaemia (AML) who harbour an FLT3 mutation, in combination with standard chemotherapy comprising daunorubicin and cytarabine for induction and high-dose cytarabine chemotherapy for consolidation, followed by Rydapt® monotherapy as maintenance treatment in patients in complete remission

• There is considerable added benefit for midostaurin in combination with standard chemotherapy comprising daunorubicin and cytarabine for induction, midostaurin in combination with high-dose cytarabine chemotherapy for consolidation, and midostaurin as monotherapy for maintenance treatment in adult patients with newly diagnosed, FLT3-positive acute myeloid leukaemia (AML), there is a considerable additional benefit.
• mortality
  • Overall survival was defined in the RATIFY trial as the time from randomisation to the patient’s death, regardless of the underlying cause of death.
  • Treatment with midostaurin resulted in a statistically significant advantage in overall survival compared with placebo (hazard ratio = 0.77 [0.63; 0.95], one-sided p-value = 0.0078).
  • The magnitude of the median survival time in months, including its absolute difference, cannot be validly assessed due to a plateau effect in the Kaplan-Meier curves in the region of a 50% event rate.
  • The difference in 5-year survival was 8% in favour of midostaurin, with a 95% confidence interval of 15% to 0.7%.
  • Overall, treatment with midostaurin results in an advantage in the mortality endpoint category compared with placebo.
  • The addition of midostaurin results in an improvement in long-term survival compared with previously used treatment regimens.
  • Against this background, the effect of midostaurin on survival time is regarded as a considerable improvement.
• Morbidity – Recurrences/Disease-Free Survival
  • In accordance with the operationalisation in the RATIFY study, only patients who achieved complete remission within 60 days of the start of induction therapy were included in the analysis of disease-free survival.
  • As the selection of patients with complete remission constituted a breach of randomisation, a high degree of bias in the results must be assumed.
  • In the RATIFY study, disease-free survival was defined as the time from achieving complete remission within 60 days of the start of induction therapy until the occurrence of a relapse or the patient’s death.
  • Consolidation therapy to prevent a (rapid) relapse is absolutely essential for patients with AML.
  • It cannot therefore be ruled out that, for a significant proportion of patients, relapses were also recorded before the completion of consolidation therapy.
  • Consequently, in addition to the aforementioned breach of randomisation, further significant uncertainties arise regarding the validity and thus the interpretation of the results.
  • The survival analysis reveals a statistically significant difference between the treatment arms (hazard ratio = 0.71 [0.55; 0.92], p-value = 0.0051).
  • The median difference in disease-free survival for midostaurin compared with placebo is 11.23 months.
  • Consequently, the result on disease-free survival, which shows an advantage for midostaurin, is used only as supplementary evidence in the overall assessment: it supports the finding regarding the extent of the additional benefit, which remains unchanged as a result.
• quality of life
  • No assessment of health-related quality of life was carried out in the RATIFY trial.
• Side effects
  • In the North American centres, side effects were recorded only for adverse events graded CTCAE 3–4, with the exception of 13 predefined adverse events.
  • Adverse events (AEs) occurred in almost all patients.
  • With regard to serious AEs of CTCAE grade 3–4, severe AEs and AEs leading to therapy discontinuation, there were no statistically significant differences between the treatment arms.
  • With regard to adverse events of CTCAE grade 3–4 occurring at a frequency of >10% , an overall analysis of the three treatment phases reveals a statistically significant difference to the detriment of midostaurin compared with placebo for the endpoints of exfoliative dermatitis and device-associated infections.
  • Overall, midostaurin is associated with a disadvantage in terms of side effects, due to an increase in the specific adverse events (CTCAE grade 3–4) of exfoliative dermatitis and device-associated infections.
• Overall assessment
  • For the benefit assessment of midostaurin in combination with standard chemotherapy comprising daunorubicin and cytarabine for induction, and midostaurin in combination with high-dosechemotherapy with cytarabine for consolidation, and midostaurin as monotherapy for maintenance treatment in adult patients with newly diagnosed, FLT3-positive acute myeloid leukaemia (AML), results from the RATIFY trial are available for the endpoint categories of mortality, morbidity and side effects.
  • Treatment with midostaurin resulted in a statistically significant advantage in overall survival and the 5-year survival rate compared with placebo, which is interpreted as a moderate prolongation of survival.
  • With regard to disease-free survival, midostaurin shows an advantage compared with placebo.
  • However, as there are relevant uncertainties regarding the validity and thus the interpretation of the results, due to the current definition of disease-free survival and the breach of randomisation, the finding on disease-free survival is only used as supplementary evidence: it supports the finding regarding the extent of the additional benefit, which remains unchanged as a result.
  • It is not possible to assess the impact of midostaurin on disease-specific symptoms and health-related quality of life, as neither the patients’ symptoms nor their health-related quality of life were recorded in the RATIFY study.
  • With regard to side effects, there is an increased incidence of certain severe adverse events (CTCAE Grade 3–4) during treatment with midostaurin: exfoliative dermatitis and device-associated infections.
  • In summary, a significant improvement in treatment-related benefit, not previously achieved, has been observed, as a moderate prolongation of survival has been achieved.

b) Rydapt® is used: as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasia (SM-AHN) or mast cell leukaemia (MCL).

• mortality
  • Overall survival was defined in both studies as the time from the start of treatment until the patient’s death, regardless of the underlying cause of death.
  • In the CPKC412D2201 study, the median follow-up duration was 43 months, whereas in the supportive CPKC412A2213 study, the median follow-up was 73 months.
  • In the CPKC412D2201 study, the median survival was 28.7 months for the ‘Full Analysis Set (FAS)’ population and 26.8 months for the ‘Primary Efficacy (PEP)’ population.
  • In the CPKC412A2213 study, the median survival was 40 months.
  • Based on data from the PEP population of the CPKC412D2201 study for the individual disease subtypes, the median survival for patients with ASM was 51.1 months. Patients with SM-AHN survived for a median of 20.7 months and patients with MCL for 9.4 months.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was defined in both studies as the time from the start of treatment to the first confirmed progression or to the patient’s death, regardless of the underlying cause of death.
  • In the CPKC412D2201 study, the median PFS was 17 months, and in the CPKC412A2213 study, it was 38.6 months.
  • In the CPKC412D2201 study, the median PFS had not been reached at the time of data cut-off for patients with ASM. Patients with SM-AHN had a median PFS of 11 months, and patients diagnosed with MCL had a median PFS of 11.3 months.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the overall survival endpoint. It remains unclear on the basis of which criteria the ‘disease progression’ component of the morbidity endpoint was assessed.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • Quality of life was documented only in the CPKC412D2201 study. It was assessed descriptively using the SF-12 questionnaire, based on the change from baseline.
  • Patients in the study had a significantly impaired quality of life at baseline, with a mean score of less than 50. The mean change from baseline to cycle 6 in the analysis of the FAS population was 6.6 points for the PCS and 4.9 points for the MCS. In the analysis of the PEP population, the change from baseline to cycle 6 was 6.4 points for the PCS and 4.7 points for the MCS.
  • Compared with the analysis after 6 cycles, the FAS population showed a deterioration in the mean change from baseline to cycle 12 for both the PCS and the MCS (PCS = 5.7 points; MCS = 4.5 points). This effect is also evident for the MCS in the PEP population (3.6 points).
  • As there is no known clinical threshold for either the PCS or the MCS, and given the potential for data bias, no valid conclusions can be drawn based on the SF-12 results.
• Side effects
  • Adverse events (AEs) occurred at least once in almost all study participants receiving midostaurin.
  • AEs of CTCAE grade 3–4 occurred in 88.8% (CPKC412D2201) and 61.5% (CPKC412A2213) of patients, respectively. Serious AEs were observed in 73.3% (CPKC412D2201) and 46.2% (CPKC412A2213) of patients, respectively.
  • In the CPKC412D2201 study, 25.9% of patients had to discontinue the study due to AEs, compared with 15.4% in the CPKC412A2213 study.
  • In the CPKC412D2201 study, the most common AEs, occurring in over 30% of patients, included disorders of the blood and lymphatic system, disorders of the gastrointestinal tract, and general disorders and administration site conditions. In the CPKC412A2213 study, disorders of the nervous system were also present with an incidence of over 30%.
  • Severe AEs of CTCAE Grade 3–4 with an incidence of more than 10% in the CPKC412D2201 study were haematological abnormalities (anaemia, thrombocytopenia and neutropenia). In the CPKC412A2213 study, hyperglycaemia with an incidence of > 10% and CTCAE grade 3–4 was observed in patients instead of neutropenia.
• Overall assessment
  • Data are available from the pivotal registration trial CPKC412D2201 to assess the extent of the additional benefit of midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasia (SM-AHN) or mast cell leukaemia (MCL), results on mortality, morbidity, quality of life and side effects are available from the pivotal registration trial CPKC412D2201. In addition, data on mortality and side effects are available from the supportive registration study CPKC412A2213.
  • Due to the single-arm study design, no comparative conclusions can be drawn regarding the therapeutic effects of midostaurin. The clinical relevance of the results regarding mediator-related symptoms from baseline to cycle 12 remains unclear, given the potential bias in the results, the lack of data for a large proportion of patients and the increase in the frequency of numerous symptoms by cycle 24.
  • Furthermore, no valid conclusions can be drawn from the analysis of the questionnaires on symptoms and health-related quality of life compared with baseline, due to the only minor changes, the potential bias in the data and the absence of clinical relevance thresholds.
  • In the present case, the key factor relevant to decision-making is the limited evidence base, which does not permit a valid assessment of the results.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit based on the data presented are not possible.

Courtesy translation only, please refer to the German original.