Daratumumab (1) – Darzalex®

• Clinical trials
  • The SIRIUS trial is a multicentre, multinational, open-label, single-arm Phase II trial in patients with relapsed and refractory multiple myeloma.
  • The GEN501 supportive study is a multicentre, multinational, open-label Phase I/II study in patients with relapsed and refractory multiple myeloma to investigate the tolerability of daratumumab.

a) 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 course of treatment

• The G-BA assesses the extent of the additional benefit of daratumumab—to be attributed solely from a legal perspective under Section 35a(1), sentence 10, first half-sentence, SGB V, to be assumed from a purely legal perspective, as non-quantifiable on the basis of 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.
• An additional benefit exists in accordance with Section 35a(1), sentence 10, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• In the present case and for this indication, the particularly limited evidence base is a key factor in the decision, meaning that a valid assessment of the results to quantify the additional benefit is not possible.
• Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data provided.
• mortality
  • In the SIRIUS study, overall survival was assessed as a secondary endpoint. Overall survival was defined as the time from the day of the first administration of the study medication until death, regardless of the underlying cause of death.
  • The median overall survival time (2nd data cut-off) was 17.5 months [95% CI: 13.7 – n.a.].
  • Due to the single-arm design of the study, the pharmaceutical manufacturer presented both a non-adjusted indirect comparison and a matching-adjusted indirect comparison, neither of which were considered suitable for demonstrating additional benefit. Consequently, the results do not permit a quantitative assessment of the effects in terms of the extent of the additional benefit.
• morbidity
  • Response
  • The ‘overall response rate’ (ORR) was defined as the proportion of patients who achieved complete remission (CR) or partial remission (PR) according to IMWG criteria.
  • Based on the pharmaceutical manufacturer’s explanations, it remained unclear whether the recording of soft-tissue manifestations was carried out in conjunction with the reporting of pain or other patient-relevant symptoms. Consequently, the ORR was not recorded on a symptom-specific basis. Therefore, this endpoint alone is not considered to be directly relevant to patients.
  • PFS
  • The secondary endpoint PFS was defined as the time from the first administration of the study medication until disease progression or death.
  • In accordance with the operationalisation, the morbidity component ‘disease progression’ was not recorded on a symptom-based basis, but rather using imaging and laboratory procedures, as, as with the ORR, it remained unclear whether the recording of soft-tissue manifestations in the context of progression was linked to reports of pain or other patient-relevant symptoms.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. The overall conclusion regarding the extent of the additional benefit remains unaffected.
• quality of life
  • Data on endpoints in the quality of life category were not collected in the SIRIUS study.
• Side effects
  • Adverse events occurred at least once in almost all patients.
  • Adverse events of grade ≥3 according to the CTCAE were also observed, as well as adverse events that led to discontinuation of the study medication or to death.
  • For the ‘side effects’ endpoint, the pharmaceutical manufacturer submitted a non-adjusted indirect comparison, which, as described under the ‘overall survival’ endpoint, must be regarded as invalid. Consequently, the results presented for the ‘side effects’ endpoint do not permit a quantitative assessment of the effects.
• Conclusion
  • Taking the available results as a whole, the G-BA arrives at the following assessment of the extent of the additional benefit: an additional benefit exists in accordance with Section 35a(1), sentence 10, first half-sentence, SGB V, but it is non-quantifiable because the available scientific data do not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.

Courtesy translation only, please refer to the German original.