Luspatercept (5) – Reblozyl®

• Clinical trials
  • For the benefit assessment of the active ingredient luspatercept, the pharmaceutical manufacturer submitted the results of the pivotal MEDALIST trial (ACE-536-MDS-001). This was a double-blind, randomised, controlled, multicentre Phase III trial.

Adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS) with ring sideroblasts, classified as very low, low or intermediate risk, who have not responded satisfactorily to erythropoietin-based therapy or are unsuitable for such treatment

• An additional benefit is not proven.
• In the overall assessment of the available results for patient-relevant endpoints, the additional benefit of luspatercept over the appropriate comparator therapy is not proven.
• mortality
  • Overall survival is defined as the time from randomisation to death from any cause or to censoring of the patient.
  • There is no statistically significant difference between the treatment arms.
• Morbidity – avoidance of transfusions (transfusion-free period)
  • The endpoint ‘transfusion avoidance’ is defined as a period without red blood cell (RBC) concentrate transfusions for a specified duration during the course of the study.
  • With regard to the proportion of patients achieving transfusion avoidance for ≥ 24 weeks, there is a statistically significant advantage in favour of treatment with luspatercept + BSC compared with placebo + BSC. Transfusion avoidance of ≥ 24 weeks was observed in 20 participants (13.1 %) in the intervention arm and in one participant (1.3 %) in the control arm.
  • However, this advantage is not reflected in other endpoints that might, in principle, be associated with avoiding transfusions. In particular, a disadvantage is evident for the ‘Physical Functioning’ subscale of the EORTC QLQ-C30.
  • Overall, based on these results regarding the avoidance of transfusions for ≥ 24 weeks, a statistically significant advantage in favour of treatment with luspatercept + BSC can be identified with regard to long-term avoidance of transfusions.
  • However, in the present case, taking into account the results for the other endpoints, the extent of this difference is considered too minor for this finding to justify the conclusion of additional benefit at the endpoint level in the overall assessment.
• Health-related quality of life – Physical functioning
  • Health-related quality of life was assessed using the functional scales and the global health status scale (overall assessment) of the cancer-specific EORTC QLQ-C30 questionnaire.
  • There was no statistically significant difference between the treatment arms in terms of improvement in health-related quality of life. In contrast, there was a statistically significant difference in favor of the luspatercept treatment in terms of the deterioration in physical functioning.
  • However, this disadvantage is not reflected in any other subscale of the EORTC QLQ-C30. Overall, neither an advantage nor a disadvantage of luspatercept + BSC compared with placebo + BSC can be inferred in the ‘quality of life’ category.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of luspatercept in the treatment of adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS) with ring sideroblasts, classified as very low, low or intermediate risk, who have not responded satisfactorily to erythropoietin-based therapy or are unsuitable for it, results are available for the endpoint categories of mortality, morbidity, quality of life and side effects from the MEDALIST study comparing luspatercept plus best supportive care (BSC) with placebo plus BSC.
  • There is no statistically significant difference between the treatment arms in terms of overall survival. In the morbidity endpoint category, luspatercept plus BSC shows an advantage in terms of symptom worsening for the insomnia endpoint and a disadvantage for the fatigue endpoint.
  • For the morbidity endpoint category, results on the avoidance of transfusions are available. For patients within the therapeutic indication, the long-term or sustained avoidance of transfusions represents a primary treatment goal, through which control of anaemia and anaemia--related symptoms whilst remaining free from red blood cell concentrate transfusions. For the present assessment, a period of transfusion avoidance of ≥ 24 weeks is regarded as the relevant timeframe for assuming long-term avoidance of transfusions.
  • With regard to the proportion of patients achieving a transfusion-free period of ≥ 24 weeks, there is a statistically significant advantage in favour of treatment with luspatercept + BSC compared with placebo + BSC. However, this advantage is not reflected in other endpoints that might, in principle, be associated with transfusion avoidance. In particular, a disadvantage is observed for the ‘Physical Functioning’ subscale of the EORTC QLQ-C30. Overall, therefore, based on these results regarding the avoidance of transfusions for ≥ 24 weeks, a statistically significant advantage in favour of treatment with luspatercept + BSC can be identified with regard to the long-term avoidance of transfusions.
  • However, in this case, taking into account the results for the other endpoints, the extent of this difference is considered too minor for this finding to justify the conclusion of additional benefit at the endpoint level in the overall assessment.
  • With regard to side effects, no overall advantage or disadvantage can be identified for luspatercept + BSC compared with placebo + BSC.
  • In detail, a disadvantage is observed in terms of severe AEs (CTCAE grade ≥ 3) in the system organ class ‘nervous system disorders’.
  • Luspatercept may represent a relevant treatment option for individual patients within the indicated therapeutic indication.
  • In the overall assessment of the available results for patient-relevant endpoints, the additional benefit of luspatercept over the appropriate comparator therapy is not proven.

Courtesy translation only, please refer to the German original.