Carfilzomib (3) – Kyprolis®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer refers in the dossier to the results of the randomised, open-label, controlled Phase III ASPIRE trial.
  • The trial compared carfilzomib in combination with lenalidomide and dexamethasone against lenalidomide in combination with dexamethasone.
  • For the benefit assessment, the pharmaceutical manufacturer refers in the dossier to the results of the randomised, open-label, controlled Phase III ENDEAVOR trial.
  • The study compared carfilzomib in combination with dexamethasone against bortezomib in combination with dexamethasone.

a) Carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have already received at least one prior therapy.

• There is a hint of considerable additional benefit for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have already received at least one prior therapy.
• Overall, for carfilzomib in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone in the treatment of patients with multiple myeloma who have received at least one prior course of treatment, there is a hint of considerable additional benefit.
• On balance, for these reasons, the certainty of the evidence for the established additional benefit is classified as a hint.
• mortality
  • In the ASPIRE trial, a statistically significant advantage was observed for the endpoint of overall survival with carfilzomib in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone (hazard ratio = 0.794, 95% CI [0.667; 0.945], p-value = 0.009).
  • The median survival time in the intervention group was 48.3 months, which is 7.9 months longer than in the control group (40.4 months).
  • Subgroup analyses provide proof of an effect modification by the characteristic of age (interaction: p = 0.048).
  • For the present assessment, the result for the study’s overall population is therefore used. The advantage in overall survival demonstrated for carfilzomib in combination with lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone is assessed as a moderate prolongation of survival.
• Morbidity – Progression-free survival (PFS)
  • In the ASPIRE trial, PFS was the primary endpoint and was defined as the time from randomisation to the first documented evidence of progression or death from any cause in the patient.
  • The median PFS was 26.3 months in the intervention arm compared with 17.6 months in the control arm. Overall, based on the survival analyses, there was a statistically significant difference between carfilzomib in combination with lenalidomide and dexamethasone and lenalidomide in combination with dexamethasone (hazard ratio = 0.690 [0.570; 0.834]; p<0.0001).
  • 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 secondary endpoint of overall survival. The morbidity component ‘disease progression’ was assessed according to IMWG criteria and was therefore not symptom-based, but rather determined using laboratory parameters, imaging and haematological procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected by this.
• Morbidity – Symptoms
  • The symptom scales of the EORTC-QLQ-C30 questionnaire and the myeloma-specific supplementary tool EORTC QLQ-MY20 were used to assess symptoms.
  • With regard to the endpoint of constipation, there is a statistically significant difference in favour of carfilzomib in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone.
  • Analysis of the time to a deterioration of at least 10 points for the endpoint ‘loss of appetite’ revealed a statistically significant difference to the detriment of carfilzomib in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone; although the extent of the effect is no more than minimal.
  • For other symptom-related endpoints, there is no statistically significant difference between the treatment groups.
  • An overall review of the results regarding the symptoms assessed reveals a minor advantage for carfilzomib in combination with lenalidomide and dexamethasone over lenalidomide in combination with dexamethasone in one specific aspect (constipation).
• Health-related quality of life
  • Health-related quality of life was assessed using the functional scales of the disease-specific EORTC QLQ-C30 instrument and the myeloma-specific EORTC QLQ-MY20 supplement.
  • With regard to the endpoint of global health status, there was a statistically significant difference in favour of the carfilzomib combination therapy compared with lenalidomide in combination with dexamethasone.
  • For other health-related quality of life endpoints, there was no statistically significant difference between the treatment groups.
  • Overall, the results show a minor advantage for carfilzomib in combination with lenalidomide and dexamethasone over lenalidomide in combination with dexamethasone in one aspect of quality of life (global health status).
• Side effects – serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3), discontinuation due to AEs
  • There were no statistically significant differences between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs. Consequently, there is no proof of either an advantage or a disadvantage for carfilzomib in combination with lenalidomide and dexamethasone with regard to these endpoints.
• Overall assessment
  • For the assessment of the additional benefit of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy, the ASPIRE trial provides results on mortality (overall survival), morbidity, health-related quality of life and side effects compared with combination therapy comprising lenalidomide and dexamethasone.
  • With regard to overall survival, there is a statistically significant advantage for treatment with carfilzomib in combination with lenalidomide and dexamethasone, which is assessed as a moderate prolongation of survival.
  • With regard to symptoms and health-related quality of life, treatment with carfilzomib in combination with lenalidomide and dexamethasone shows minor advantages compared with lenalidomide in combination with dexamethasone.
  • The available results regarding side effects show no disadvantages associated with treatment with carfilzomib in combination with lenalidomide and dexamethasone compared with treatment with lenalidomide in combination with dexamethasone. No conclusions can be drawn regarding specific adverse events, as no usable data are available.

b) Carfilzomib in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have already received at least one prior therapy.

• There is a hint of considerable additional benefit for carfilzomib in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have already received at least one prior therapy.
• Overall, there is a hint of considerable additional benefit for carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior course of treatment.
• On balance, for these reasons, the certainty of the evidence for the established additional benefit is classified as a hint.
• mortality
  • In the ENDEAVOR trial, a statistically significant advantage was observed for carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone for the endpoint of overall survival (hazard ratio = 0.791, 95% CI [0.648; 0.964], p-value = 0.02).
  • The median survival time in the intervention group was 47.6 months, which is 7.6 months longer than in the control group (40.0 months).
  • The advantage in overall survival demonstrated for carfilzomib in combination with dexamethasone compared with bortezomib and dexamethasone is assessed as a moderate prolongation of survival.
• Morbidity – Progression-free survival (PFS)
  • In the ENDEAVOR trial, PFS was the primary endpoint and was defined as the time from randomisation to the first documented evidence of progression or death from any cause in the patient.
  • The median PFS was 18.7 months in the intervention arm compared with 9.4 months in the control arm. Overall, based on the survival analyses, there was a statistically significant difference between carfilzomib in combination with dexamethasone and bortezomib in combination with dexamethasone (hazard ratio = 0.533 [0.437; 0.651]; p<0.0001).
  • 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 secondary endpoint of overall survival. The ‘disease progression’ component of morbidity was assessed according to IMWG criteria and was therefore not symptom-based, but rather determined using laboratory parameters, imaging and haematological procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected by this.
• Morbidity – Symptoms
  • The symptom scales of the EORTC-QLQ-C30 questionnaire and the myeloma-specific supplementary tool EORTC QLQ-MY20 were used to assess symptoms.
  • The analysis shows a statistically significant difference in favour of carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone in terms of the time to a deterioration of at least 10 points on the insomnia endpoint; although the extent of the effect is no more than minimal.
  • With regard to the endpoints of loss of appetite, diarrhoea, constipation, nausea/vomiting and disease-related side effects, statistically significant advantages were observed for carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone.
  • For other symptom-related endpoints, there is no statistically significant difference between the treatment groups.
  • An overall review of the results on the symptoms assessed reveals positive effects on individual symptoms with carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone.
• Health-related quality of life
  • Health-related quality of life was assessed using the functional scales of the disease-specific EORTC QLQ-C30 instrument and the myeloma-specific EORTC QLQ-MY20 supplement.
  • For the endpoints of global health status, cognitive functioning, physical functioning and social functioning, a statistically significant effect was observed in favour of carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone.
  • For other endpoints related to quality of life, there was no statistically significant difference between the treatment groups.
  • An overall review of the quality of life results shows positive effects of carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, there was a statistically significant difference to the detriment of carfilzomib in combination with dexamethasone compared with bortezomib in combination with dexamethasone.
• Overall assessment
  • For the assessment of the additional benefit of carfilzomib in combination with dexamethasone for the treatment of patients who have received at least one prior therapy, the ENDEAVOR study provides results on mortality (overall survival), morbidity, health-related quality of life and side effects compared with combination therapy with bortezomib and dexamethasone.
  • With regard to overall survival, there is a statistically significant advantage for treatment with carfilzomib in combination with dexamethasone, which is assessed as a moderate prolongation of survival.
  • In addition, there are some positive effects on disease- and treatment-specific symptoms, as well as hints of improvements in health-related quality of life.
  • In the endpoint category of side effects, the carfilzomib combination therapy is associated with disadvantages due to an increase in serious adverse events. No conclusions can be drawn regarding specific adverse events, as no usable data are available.
  • The assessment of the disadvantages relating to side effects takes particular account of the results on health-related quality of life and the results on therapy discontinuations due to adverse events, which do not show any statistically significant difference.

Courtesy translation only, please refer to the German original.