Luspatercept (2) – Reblozyl®

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

Adult patients 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

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• The strength of the evidence is classified as ‘hint’.
• mortality
  • overall survival
  • Overall survival is defined as the time from randomisation until death from any cause or until the patient is censored.
  • There is no statistically significant difference between the treatment arms.
• Morbidity – Transfusion-free period
  • The endpoint ‘transfusion-free period’ 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 analyses of the various periods of transfusion-free survival, for the purposes of this assessment, a transfusion-free period of ≥ 24 weeks is considered the relevant timeframe for inferring long-term avoidance of transfusions (transfusion-free survival).
  • With regard to the proportion of patients with a period of transfusion-free status of ≥ 24 weeks, there is a statistically significant advantage in favour of treatment with luspatercept + BSC compared with placebo + BSC. A transfusion-free period of ≥ 24 weeks was observed in 20 patients (13.1 %) in the intervention arm and in one patient (1.3 %) in the control arm.
  • However, this advantage is not reflected in other endpoints that might, in principle, be associated with a transfusion-free period. In particular, a disadvantage on health-related quality of life (the physical functioning subscale of the EORTC QLQ-C30) is evident.
  • Overall, based on these results regarding transfusion-free periods of ≥ 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 (transfusion-free status).
  • 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
  • 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 to the disadvantage of the luspatercept treatment in terms of the deterioration in physical functioning.
  • Overall, the results indicate that, in terms of health-related quality of life, the Luspatercept + BSC group had a disadvantage compared to the placebo + BSC group in terms of the deterioration in physical functioning.
• Side effects
  • Total adverse events (AEs)
  • AE occurred in almost all study participants. The results are presented here for supplementary information only.
  • Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs
  • There were no statistically significant differences between the treatment arms for the endpoints SAEs, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • AE of particular interest
  • With regard to the AE of particular interest ‘premalignant condition’ (SOC, AE), two events occurred in the intervention arm and three in the control arm. The adverse event of particular interest ‘malignancies’ (SOC, AE) occurred in five patients in the intervention arm and in one patient in the control arm. Due to the minor number of events, no comparative analyses were carried out.
  • An overall review of the results for the ‘side effects’ endpoint category reveals neither an advantage nor a disadvantage for luspatercept + BSC compared with placebo + BSC.
• Overall assessment
  • For the assessment of the additional benefit of luspatercept for the treatment of adult patients 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 not suitable for it, results are available from the MEDALIST study for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • In this ongoing study, luspatercept plus best supportive care (BSC) is being compared 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 showed 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 freedom from transfusion are available. For patients with a therapeutic indication, the long-term or sustained avoidance of transfusions (transfusion-free status) a primary therapeutic goal, enabling the control of anaemia and anaemia-related symptoms whilst remaining free from red blood cell concentrate transfusions. For the present assessment, a period of freedom from transfusion of ≥ 24 weeks is regarded as the relevant timeframe for assuming long-term avoidance of transfusions (freedom from transfusion).
  • With regard to side effects, no advantage or disadvantage can be identified for luspatercept + BSC compared with placebo + BSC.
  • In its overall assessment of the available results on patient-relevant endpoints, the G-BA rates the extent of the additional benefit of luspatercept in the treatment of adult patients with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS) with ring sideroblasts, with very low, low or intermediate risk, who have not responded satisfactorily to erythropoietin-based therapy or are not suitable for it, as being very low, low or intermediate, respectively, on the basis of the criteria set out in Section 5(8), first sentence, 2 in conjunction with Section 5(7), first sentence, number 4 of the AM-NutzenV, as non-quantifiable, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.