Daratumumab (13) – Darzalex®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data for the benefit assessment from the open-label, randomised, controlled Phase III ANDROMEDA trial, in which daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone against bortezomib in combination with cyclophosphamide and dexamethasone (VCd).

a1) Adults with newly diagnosed systemic light-chain (AL) amyloidosis for whom bortezomib in combination with cyclophosphamide and dexamethasone represents the appropriate treatment on an individual patient basis

• Overall, there is a hint of considerable additional benefit from daratumumab + VCd compared with VCd.
• Consequently, the G-BA identifies a substantial added benefit for daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone for the treatment of newly diagnosed systemic light-chain (AL) amyloidosis, in adult patients, whereas bortezomib in combination with cyclophosphamide and dexamethasone represents a considerable additional benefit on a patient-by-patient basis.
• Overall, therefore, the certainty of the evidence for the established additional benefit is classified as ‘hint’.
• mortality
  • Overall survival is defined in the ANDROMEDA study as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of daratumumab in combination with VCd compared with VCd alone.
  • The extent of the prolongation in overall survival achieved is assessed as a marked improvement.
• Morbidity – severe organ damage
  • The composite endpoint of severe organ damage is defined as the time from randomisation to the occurrence of any of the following events: clinical manifestation of heart failure, defined as the need for a heart transplant, a left ventricular assist device, or an intra-aortic balloon pump; clinical manifestation of renal failure, defined as the development of end-stage renal disease (requiring haemodialysis or a kidney transplant).
  • For the endpoint of severe organ damage, there is a statistically significant advantage in favour of daratumumab + VCd.
  • The results are influenced in particular by the component relating to the clinical manifestation of renal failure.
  • Given the minor event rates (1.5% versus 5.7%), the extent of the effect is assessed as a relevant, but no more than a minor, improvement.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • In the ANDROMEDA study, patients’ symptoms are assessed using the symptom scales of the EORTC-QLQ-C30 questionnaire.
  • The pharmaceutical manufacturer presents responder analyses in the dossier showing a change of ≥ 10 points for the time to first deterioration and for the time to first improvement.
  • Given the expected course of the disease in this therapeutic indication and taking into account the distribution of the absolute scale scores at the start of the study, the responder analyses showing a change of ≥ 10 points for the time to first deterioration are used for this assessment.
  • This reveals a statistically significant advantage for daratumumab in combination with VCd in terms of time to worsening of dyspnoea.
  • No statistically significant differences were observed for the other symptom scales.
• Morbidity – Symptoms (individual items of the EORTC QLQ Ovarian Cancer 28 (OV28), Multiple Myeloma 20 (MY20) and Prostate Cancer 25 (PR25))
  • In addition to the results for the EORTC QLQ-C30, the pharmaceutical manufacturer presents results in the dossier for the pre-specified EORTC individual items: ‘tingling in the hands and feet’ from the EORTC QLQ-MY20, ‘feeling of fullness in the stomach/abdomen’ from the EORTC QLQ-OV28, and ‘swelling of the legs or ankles’ from the EORTC QLQ-PR25.
  • The pharmaceutical manufacturer has provided a clear justification for the selection of the pre-specified individual items.
  • The pharmaceutical manufacturer presents responder analyses in the dossier showing a change of ≥ 10 points for the time to first deterioration and for the time to first improvement.
  • Given the expected course of the disease in the indicated therapeutic indication and taking into account the distribution of the absolute scale scores at the start of the study, the responder analyses showing a change of ≥ 10 points in the time to first deterioration are used for this assessment.
  • None of the analyses presented show a statistically significant difference between the treatment arms.
• Quality of life – EORTC QLQ-C30
  • In the ANDROEMDA study, health-related quality of life is assessed, on the one hand, using the functional scales and the global health status scale of the EORTC QLQ-C30.
  • In line with the comments in the ‘Symptoms’ section, the analyses are based on the time to first deterioration.
  • No statistically significant difference was observed between the treatment arms.
• Side effects – Total adverse events (AEs)
  • Almost all patients in the ANDROMEDA study experienced an adverse event.
  • The results for this endpoint are presented for supplementary information only.
• Overall assessment
  • Results are available from the ANDROMEDA study for the assessment of the additional benefit of daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone in adults with newly diagnosed systemic light-chain(AL) amyloidosis, for whom bortezomib in combination with cyclophosphamide and dexamethasone represents the appropriate treatment on an individual patient basis, results from the ANDROMEDA study are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • With regard to overall survival, a statistically significant advantage was observed in this patient group in favour of daratumumab in combination with VCd compared with VCd alone.
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
  • In the morbidity endpoint category, there is an advantage for daratumumab in combination with VCd for the endpoint of severe organ damage, which is supported by a further advantage on the dyspnoea symptom scale.
  • With regard to health-related quality of life, the available data do not, on the whole, reveal any differences between the treatment arms that are relevant to the assessment.
  • With regard to side effects, the overall rates of serious side effects (SAEs), severe side effects (CTCAE grade ≥ 3) and therapy discontinuations due to side effects show no differences between the treatment arms that are relevant to the benefit assessment.
  • In detail, with regard to specific adverse events, there is both a disadvantage for the endpoint ‘skin and subcutaneous tissue disorders’ (SOC, AE) and an advantage for the endpoint ‘hypokalaemia’ (PT, severe AE).
  • When the available results are considered as a whole, the advantage observed for the endpoint ‘overall survival’ and the advantage for the endpoint ‘severe organ damage’—which is supported by a further advantage on the dyspnoea symptom scale—are not offset by any disadvantages.

a2) Adults with newly diagnosed systemic light-chain (AL) amyloidosis for whom a treatment other than bortezomib in combination with cyclophosphamide and dexamethasone constitutes the appropriate treatment on an individual patient basis

• The findings of the resolution of 20 January 2022 regarding patient population a2) remain unaffected by this.

Courtesy translation only, please refer to the German original.