Daratumumab (3) – Darzalex®

• Clinical trials
  • In the POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (DRd) was compared with lenalidomide in combination with dexamethasone (Rd).
  • In the CASTOR trial, treatment with daratumumab in combination with bortezomib and dexamethasone (DVd) was compared with the combination therapy of bortezomib and dexamethasone (Vd).

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

• Indication of considerable additional benefit.
• On balance, the findings regarding side effects are not considered serious, given that there is no deterioration in patients’ quality of life and in view of the severity of the disease.
• Taking into account the uncertainties described, there is overall evidence for an indication of an additional benefit from daratumumab.
• mortality
  • For the endpoint of overall survival, there is a statistically significant advantage of the daratumumab combination therapy over lenalidomide and dexamethasone or bortezomib and dexamethasone (hazard ratio (meta-analysis) = 0.63 [0.47; 0.84], p-value = 0.002).
  • The median survival time had not been reached in either arm of both the POLLUX and CASTOR trials at the second data cut-off on 30 June 2016.
  • Consequently, the advantage in overall survival demonstrated for daratumumab combination therapies compared with lenalidomide or bortezomib in combination with dexamethasone is assessed as a moderate prolongation of survival.
• Morbidity – Progression-free survival (PFS)
  • In the POLLUX trial, the median PFS had not been reached in the daratumumab arm at the time of the second data cut-off. For the control arm, the median PFS was 17.51 months. The survival analysis shows a statistically significant difference between daratumumab in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone (hazard ratio = 0.37 [0.28; 0.50], p-value < 0.0001).
  • In the CASTOR trial, the median PFS at the second data cut-off in the control arm was 7.06 months. In the intervention arm (DVd), the median PFS had not yet been reached. The survival analysis revealed a statistically significant difference between daratumumab in combination with bortezomib and dexamethasone compared with the combination therapy of bortezomib and dexamethasone (hazard ratio = 0.33 [0.26; 0.43], p-value < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
• Morbidity – Health status (EQ-5D VAS)
  • The analysis of the time to a deterioration of at least 7 or 10 points shows no statistically significant effect.
  • No additional benefit of daratumumab combination therapies over lenalidomide or bortezomib in combination with dexamethasone is proven for this endpoint.
• Morbidity – Symptoms
  • Analysis of the time to deterioration by at least 10 points revealed no statistically significant difference between the treatment groups for any endpoint.
  • Accordingly, the additional benefit of daratumumab combination therapies over lenalidomide or bortezomib in combination with dexamethasone is not proven for the endpoint category ‘symptoms’.
• Health-related quality of life
  • In the meta-analytic summary, there is no statistically significant difference between the treatment arms for any endpoint relating to health-related quality of life.
  • Consequently, based on the meta-analytical evaluation, the additional benefit of daratumumab combination therapies over lenalidomide or bortezomib in combination with dexamethasone for the ‘quality of life’ endpoint category is not proven.
• Side effects
  • For the endpoint of severe AEs (CTCAE grade 3–4), there is a statistically significant effect in favor of daratumumab combination therapies (hazard ratio (meta-analysis) = 1.40 [1.22; 1.62], p-value < 0.001).
  • Furthermore, for AEs in the System Organ Classes (SOCs) ‘Gastrointestinal disorders’ and ‘Disorders of the respiratory tract, thoracic cavity and mediastinum’, as well as for the Preferred Term (PT) ‘febrile neutropenia’, there is a statistically significant disadvantage associated with daratumumab combination therapies.
  • Overall, the results on side effects show that daratumumab combination therapies have negative effects compared with lenalidomide or bortezomib in combination with dexamethasone in terms of severe AEs (CTCAE Grade 3–4) as well as for the specific AEs febrile neutropenia, gastrointestinal disorders, and disorders of the respiratory tract, thoracic cavity and mediastinum.
  • However, there are no differences in the rate of therapy discontinuation due to adverse events.
• Overall assessment
  • For the assessment of the additional benefit of daratumumab in the treatment of patients who have received at least one prior therapy, results from the POLLUX and CASTOR trials are available regarding mortality (overall survival), morbidity, health-related quality of life and side effects compared with lenalidomide or bortezomib in combination with dexamethasone.
  • With regard to overall survival, there is a statistically significant advantage of daratumumab combination therapies, which is assessed as a moderate prolongation of life.
  • With regard to health status and symptoms, there is no statistically significant difference between daratumumab combination therapies and lenalidomide or bortezomib in combination with dexamethasone.
  • In terms of side effects, the daratumumab combination therapies are associated with disadvantages in the form of an increase in severe adverse events (CTCAE Grade 3–4) and specific adverse events (febrile neutropenia, gastrointestinal disorders, and disorders of the respiratory tract, thoracic cavity and mediastinum).
  • Overall, given that there is no deterioration in patients’ quality of life and in view of the severity of the disease, the findings regarding side effects are not considered serious.

b) Daratumumab as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma who have previously been treated with a proteasome inhibitor and an immunomodulator, and who experienced disease progression during their most recent therapy.

• Additional benefit is not proven for daratumumab as monotherapy for the treatment of patients with relapsed and refractory multiple myeloma who have already been treated with a proteasome inhibitor and an immunomodulator, and who experienced disease progression during their most recent course of treatment.
• The present non-adjusted indirect comparison is unsuitable for assessing additional benefit; therefore, no additional benefit of daratumumab has been proven.
• On the basis of the evidence provided, it is not possible to make comparative statements regarding the additional benefit of daratumumab monotherapy compared with the appropriate comparator therapy specified by the G-BA for the following reasons:
• Firstly, the patient characteristics differ between the SIRIUS study and the IMF cohort in relevant respects.
• Secondly, essential information regarding the patient characteristics of those in the IMF cohort is missing.
• Irrespective of the questionable similarity between the two study populations, in a non--adjusted comparison of study results, only those differences can be used to demonstrate additional benefit which are of such a magnitude that it can be ruled out that the differences could be explained solely by the influence of confounding factors.

Courtesy translation only, please refer to the German original.