Daratumumab (7) – 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

• Hint for a minor additional benefit
• Taking the available results as a whole, the advantage observed for the endpoint of severe organ damage – which is supported by a further advantage on the dyspnoea symptom scale – is not offset by any disadvantage. Consequently, the G-BA concludes that for daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone for the treatment of newly diagnosed systemic light-chain (AL) amyloidosis, in adult patients, where bortezomib in combination with cyclophosphamide and dexamethasone represents the appropriate treatment on a case-by-case basis, the G-BA concludes that there is a minor additional benefit.
• Overall, therefore, the certainty of the evidence for the established additional benefit is classified as ‘hint’.
• mortality
  • For the endpoint of overall survival, no statistically significant difference was observed between the treatment arms.
  • An additional benefit of daratumumab in combination with VCd with regard to overall survival is therefore not proven.
• Morbidity – severe organ damage
  • The endpoint ‘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).
  • The endpoint ‘severe organ damage’ is considered patient-relevant in this operationalisation. There is a statistically significant advantage in favour of daratumumab + VCd. Given the minor event rates (0.5% vs. 3.6%), the extent of the effect is assessed as a relevant, but no more than a minor, improvement.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • Patients’ symptoms are assessed in the ANDORMEDA study using the symptom scales of the EORTC-QLQ-C30 questionnaire.
  • This reveals a statistically significant advantage for daratumumab in combination with VCd in terms of the time to worsening of dyspnoea. No statistically significant differences were observed for the other symptom scales.
• Morbidity – Symptoms (individual items from the EORTC QLQ Ovarian Cancer 28 (OV28), Multiple Myeloma 20 (MY20) and Prostate Cancer 25 (PR25))
  • According to the authors, the use of individual items as an item list is only intended in conjunction with the EORTC QLQ-C30 and a previously validated supplementary module, but not, as was done in the ANDROMEDA study, solely in conjunction with the EORTC QLQ-C30. The individual items are therefore not included in this assessment.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • In all three responder analyses (≥ 7, ≥ 10 and ≥ 15 points), there was no statistically significant difference between the treatment arms.
• Quality of life – EORTC QLQ-C30
  • A statistically significant advantage was observed for daratumumab in combination with VCd in terms of time to deterioration in emotional functioning. No statistically significant differences were observed for the other functional scales or the global health status scale.
  • Taking the results as a whole, and against this background, no relevant difference was found in health-related quality of life overall.
• Quality of life – Short Form-36 Health Survey (SF-36)
  • The analyses of the time to first deterioration show no statistically significant differences between the treatment arms, neither when using a response threshold of ≥ 5 points nor when using a response threshold of 15 per cent; this applies to both the PCS and the MCS.
• 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.
• Side effects – Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • For the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs (discontinuation of at least one active ingredient), there was no statistically significant difference between the treatment arms in any case.
• Overall assessment
  • Results from the ANDROMEDA study are available for the assessment of the additional benefit of daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone across the endpoint categories of mortality, morbidity, health-related quality of life and side effects. In this ongoing study, daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone is being compared with bortezomib in combination with cyclophosphamide and dexamethasone (VCd).
  • Despite remaining uncertainties, VCd is regarded as an adequate implementation of the appropriate comparator therapy (patient-specific therapy taking into account general health status, comorbidities and organ damage) for the study population of the ANDROMEDA trial. However, based on the study, conclusions can only be drawn regarding the additional benefit of daratumumab in combination with VCd compared with patient-specific therapy for the patient group for whom VCd represents the appropriate patient-specific therapy.
  • With regard to overall survival, no statistically significant difference between the treatment arms is observed in this patient group. An additional benefit for overall survival is therefore not proven.
  • 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, there are no differences between the treatment arms that are relevant to the benefit assessment. In detail, with regard to specific adverse events alone, 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).
  • In the overall assessment of the available results, the advantage observed for the endpoint ‘severe organ damage’—which is supported by a further advantage on the dyspnoea symptom scale—is not offset by any disadvantage.

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

• An additional benefit is not proven
• For the patient population of adult patients with newly diagnosed systemic light-chain(AL) amyloidosis, for whom a treatment other than bortezomib in combination with cyclophosphamide and dexamethasone constitutes the individually appropriate therapy, no conclusions regarding additional benefit can be drawn from the ANDROMEDA study. As only results comparing the treatment with VCd were submitted for the benefit assessment, no usable data are available overall.
• An additional benefit of daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone is not proven for patient population a2).

Courtesy translation only, please refer to the German original.