Carfilzomib (2) – Kyprolis®

• Clinical trials
  • The pivotal ENDEAVOR trial is an open-label, randomised, multicentre Phase III trial investigating the efficacy and safety of carfilzomib in combination with dexamethasone (n = 465) compared with bortezomib plus dexamethasone (n = 464) in patients with relapsed and/or progressive multiple myeloma.

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

• For adult patients with multiple myeloma who have received at least one prior course of treatment, there is minor additional benefit.
• The G-BA assesses the extent of the additional benefit of carfilzomib in combination with dexamethasone as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Taking the available results on carfilzomib into account as a whole, the G-BA concludes that the extent of the additional benefit of carfilzomib in combination with dexamethasone for patients with multiple myeloma who have received at least one prior course of treatment is minor.
• mortality
  • overall survival
  • In the 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.
  • At the time of the relevant interim analysis on 10 November 2014, the median survival time in the carfilzomib arm had not yet been reached, meaning that it was not possible to report the difference in median survival between the study arms.
  • In the carfilzomib arm, 75 (16.2%) patients died, compared with 88 (18.9%) patients in the comparator arm. The difference is not statistically significant.
  • Consequently, the results to date do not allow for an assessment of the effects in terms of the extent of the additional benefit.
• morbidity
  • PFS
  • The PFS endpoint was defined as the time from randomisation to disease progression or death, regardless of the underlying cause of death.
  • In the ENDEAVOR trial, the median progression-free survival was 18.7 months [95% CI: 15.6; n.a.] and 9.4 months [95% CI: 8.4; 10.4] in the comparator arm; HR 0.53 [95% CI: 0.44; 0.65]; 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 to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Time to the start of subsequent treatment
  • The endpoint ‘time to the start of subsequent treatment’ does not in itself constitute a patient-relevant endpoint and cannot be conclusively assessed.
  • The endpoint ‘time to the start of subsequent treatment’ is not used to assess the extent of the additional benefit.
  • Symptoms
  • No advantage was observed for treatment with carfilzomib in relation to the symptoms ‘pain’ and ‘fatigue’.
  • With regard to ‘nausea/vomiting’, an advantage was observed for carfilzomib in combination with dexamethasone. However, there are uncertainties due to the potential for bias outlined below and the lack of information on methodology.
• quality of life
  • Quality of life was assessed during the ENDEAVOR trial using the EORTC QLQ-C30, EORTC QLQ-MY20 and FACT-GOG-Ntx questionnaires.
  • The responder survival analyses are subject to a high potential for bias, as further information on the methodology – e.g. censoring rules and fulfilment of key assumptions required for conducting a Cox survival analysis – is unclear.
  • With regard to quality of life, there is an additional benefit of carfilzomib in combination with dexamethasone. However, there are uncertainties due to the identified potential for bias and the lack of information on the methodology.
• Side effects
  • Adverse events (AEs) occurred in almost all participants in the ENDEAVOR trial during the course of the study.
  • Adverse events (AEs) leading to discontinuation of study medication occurred, when adjusted for duration of exposure, statistically significantly less frequently with carfilzomib than with bortezomib.
  • When AEs were categorised according to the MedDRA System Organ Classes (SOC) and defined as those occurring with an incidence of at least 10% in one of the study arms, differences of at least 10 percentage points were observed for ‘General disorders and administration site conditions’, ‘Respiratory, thoracic and mediastinal disorders’, ‘Blood and lymphatic system disorders’, ‘vascular disorders’ and ‘cardiac disorders’ to the detriment of carfilzomib, and for the SOC ‘nervous system disorders’ to the benefit of carfilzomib.
  • Furthermore, numerical differences of more than 5 percentage points were observed for CTCAE grade ≥ 3 AEs for the preferred term ‘hypertension’ to the detriment of carfilzomib.
  • Peripheral neuropathies
  • Peripheral neuropathies of CTC grade ≥ 2 occurred in 28 (6%) patients in the treatment arm and in 146 (32%) patients in the control arm (RR 0.19 [95% CI: 0.13; 0.28]; p < 0.0001).
  • Peripheral neuropathies of CTC grade ≥ 3 occurred in 10 (2.2%) patients in the active treatment arm and in 37 (8.1%) patients in the control arm (RR 0.27 [95% CI: 0.13; 0.53]; p < 0.0001).
  • Even when taking into account the duration of exposure in the respective study arms, a statistically significant advantage was observed for carfilzomib compared with bortezomib for the endpoint of peripheral neuropathy events of grade ≥2 and ≥3.
• Overall assessment / Conclusion
  • The ENDEAVOR study provides results on the extent of the additional benefit of carfilzomib in combination with dexamethason for patients with multiple myeloma who have received at least one prior treatment (overall survival), morbidity, health-related quality of life and side effects.
  • In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this represents a previously unattained moderate—and not merely minor—improvement in treatment-related benefit, in particular due to a significant reduction in side effects, supported by data on quality of life and morbidity, taking into account the signals, particularly regarding cardiovascular risks, associated with carfilzomib.

Courtesy translation only, please refer to the German original.