Carfilzomib (1) – Kyprolis®

• Clinical trials
  • To address the question regarding the extent of the additional benefit, the pharmaceutical manufacturer submitted the ASPIRE PX-171-009 trial, on which the marketing authorisation is based. This was an open-label, controlled, randomised, multicentre and multinational Phase III trial investigating the efficacy and safety of carfilzomib, lenalidomide, dexamethasone (n=396) compared with lenalidomide and dexamethasone (n=396) in adult patients with relapsed and/or progressive multiple myeloma.

adult patients with multiple myeloma who have received at least one prior course of treatment

• For adult patients with multiple myeloma who have received at least one prior course of treatment, there is a non-quantifiable additional benefit.
• There is an additional benefit for carfilzomib in combination with lenalidomide and dexamethasone with regard to the endpoint of overall survival, but this is non-quantifiable, as the available scientific data do not currently permit a quantifiable assessment of the extent of the additional benefit for this patient-relevant endpoint.
• In the present case and indication, the decisive factor is that it was not possible to conclusively assess whether carfilzomib in combination with lenalidomide and dexamethasone offers an advantage over lenalidomide and dexamethasone in terms of patient-relevant endpoints, meaning that it is not possible to quantify the additional benefit.
• Mortality – Overall survival
  • In the ASPIRE study, overall survival was assessed as a secondary endpoint. It was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the overall survival endpoint, the results of the second, pre-planned interim analysis are available following the occurrence of a total of 305 events (corresponding to 60% of the expected events): there is a significant advantage in favour of carfilzomib with a hazard ratio (HR) of 0.79 [95% 0.63; 0.99]; p = 0.0182.
  • Although an advantage in survival must be assumed, it is not possible at this stage to quantify the difference in months, as the pre-specified median required for statistical analysis has not yet been reached in either arm.
  • The final results on mortality are still pending.
• Morbidity – PFS
  • The primary endpoint, PFS, was defined as the time from randomisation to disease progression or death, regardless of the underlying cause of death.
  • In the ASPIRE trial, the median progression-free survival in the carfilzomib arm was 26.3 months [95% CI: 23.3 – 30.5] and 17.6 months [95% CI: 15.0 – 20.6] in the comparator arm. The hazard ratio is 0.69 [95% CI: 0.57 – 0.83]; p<0.001.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint for patients.
• quality of life
  • Quality of life during the ASPIRE trial was assessed using the EORTC-QLQ-C30 and EORTC-QLQ-MY20 questionnaires.
  • Mean differences for the ‘Health Status/Quality of Life’ scale of the generic EORTC-QLQ-C30 questionnaire were statistically significant at all time points and over the entire study period of 18 carfilzomib cycles.
  • However, the clinical relevance of the difference is unclear due to the lack of validity of the thresholds for the minimum important difference (MID).
  • The differences measured using the disease-specific EORTC-QLQ-MY20 questionnaire were not significant between the two study arms (the ‘disease symptoms’ scale).
  • Although the results of the generic EORTC-QLQ-C30 questionnaire showed significant differences in favour of carfilzomib, this advantage in the carfilzomib arm could not be confirmed using the disease-specific EORTC-QLQ-MY20 questionnaire.
  • The open-label study design also makes it difficult to interpret the results.
  • With regard to quality of life, an advantage of carfilzomib in combination with lenalidomide and dexamethasone over the control intervention can be observed. Overall, however, the interpretability of the quality-of-life results is limited by methodological weaknesses and does not allow for any conclusions regarding the quantification of the extent of the additional benefit.
• Side effects
  • Adverse events (AEs) occurred at least once in almost all patients.
  • In numerical terms, more AEs were observed in the active treatment arm than in the control arm; however, the longer duration of treatment in the active treatment arm should be taken into account.
  • Statistically significant differences were observed for ‘NCI-CTCAE Grade ≥3 SAEs’ to the detriment of carfilzomib (RR 1.21 [1.05; 1.39]).
  • In several categories of adverse events of particular interest, where there was a difference of at least 5 percentage points between the two study arms (upper respiratory tract infections, thrombocytopenia, cough, diarrhoea, nausea, venous thromboembolic events), patients in the carfilzomib arm were statistically significantly more frequently affected by side effects than those in the control arm.
• Conclusion
  • Taking the available results on carfilzomib as a whole, the G-BA arrives at the following assessment of the extent of the additional benefit: There is an additional benefit for carfilzomib in combination with lenalidomide and dexamethasone with regard to the endpoint of overall survival, but this is non-quantifiable, as the available scientific evidence does not currently permit a quantifiable statement on the extent of the additional benefit for this patient-relevant endpoint.
  • The clinical relevance of the results on quality of life is unclear due to the lack of a Minimum Imaginable Difference (MID). Furthermore, there are adverse effects associated with the side effects. However, definitive study data are still pending.

Courtesy translation only, please refer to the German original.