Isatuximab (1) – Sarclisa®

• Clinical trials
  • The benefit assessment of the active ingredient isatuximab is based on the ongoing, pivotal ICARIA-MM trial. This is an open-label, randomised, controlled, multicentre Phase III trial in which the triple combination of isatuximab, pomalidomide and dexamethasone (Isa-Pd) is compared with the dual combination of pomalidomide and dexamethasone (Pd).

Adults with relapsed and refractory multiple myeloma who have received at least two prior lines of treatment, including lenalidomide and a proteasome inhibitor, and who experienced disease progression during their most recent treatment

• Overall, the G-BA concludes that there is evidence of a minor additional benefit for isatuximab in combination with pomalidomide and dexamethasone compared with pomalidomide in combination with dexamethasone.
• Consequently, the certainty of the evidence for the identified additional benefit is classified as ‘hint’.
• mortality
  • For the endpoint of overall mortality, there is no statistically significant difference between the treatment arms.
  • No additional benefit for Isa-Pd is therefore identified for the endpoint of overall survival.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the ICARIA-MM study. PFS was defined as the time from randomisation to the date of the first documented disease progression or the date of death from any cause, whichever occurred first.
  • There is a statistically significant advantage for isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd) compared with pomalidomide in combination with dexamethasone (Pd).
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of morbidity is assessed according to IMWG criteria and is therefore not symptom-based, but rather determined using laboratory parameters, imaging and haematological procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected by this.
• Morbidity – Symptoms (pain and diarrhoea)
  • With regard to the sustained worsening of disease symptoms, statistically significant differences were observed between the treatment arms for pain and diarrhoea, giving Isa-Pd an advantage over Pd.
• Morbidity – Health status
  • No statistically significant difference was observed between the treatment arms for any of the response criteria.
• Health-related quality of life – overall health status and role functioning
  • Statistically significant differences were observed between the treatment arms for overall health status and role functioning, favouring Isa-Pd over Pd.
  • However, uncertainties remain regarding the results. Accordingly, the EORTC assessment timepoints are not suitable for capturing the effects of infusion-related reactions on quality of life, as the assessment took place before the medication was administered and the infusion-related reactions therefore do not fall within the period covered by the questionnaire.
• Side effects – severe adverse events (CTCAE grade ≥ 3)
  • For the time to onset of severe AEs (CTCAE grade ≥ 3), there is a statistically significant disadvantage for Isa-Pd compared to Pd.
  • The results for the ‘side effects’ endpoint category, on which this benefit assessment is based, are therefore subject to uncertainty, particularly with regard to severe AEs.
• Side effects – Specific adverse events (bronchitis and disorders of the blood and lymphatic system)
  • For the AE ‘bronchitis’ (PT) and the severe AE (CTCAE grade ≥ 3) ‘disorders of the blood and lymphatic system’ (SOC), statistically significant differences were observed between the treatment arms, to the disadvantage of Isa-Pd compared with Pd.
• Side effects – Infusion-related reactions
  • Consequently, due to the uncertainties mentioned, no usable data are available for the endpoint ‘infusion-related reactions’ for any of the operationalisations presented.
• Overall assessment
  • In the overall assessment of the results for patient-relevant endpoints, the advantages of Isa-Pd in the endpoint categories of morbidity and health-related quality of life are offset by a disadvantage in terms of side effects. The disadvantage regarding severe adverse events (CTCAE grade ≥ 3) is considered moderate and does not reach an extent that calls into question the positive effects of Isa-Pd on disease-specific symptoms and health-related quality of life.
  • Overall, the G-BA concludes that isatuximab in combination with pomalidomide and dexamethasone for the treatment of relapsed and refractory multiple myeloma in adults who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and who experienced disease progression during their most recent treatment, offers a minor additional benefit compared with pomalidomide in combination with dexamethasone.

Courtesy translation only, please refer to the German original.