Elotuzumab (1) – Empliciti®

• Clinical trials
  • The ELOQUENT 2 trial was a randomised, multicentre, active-controlled trial with a parallel-group, open-label design.
  • The ELOQUENT 2 trial investigated elotuzumab in combination with lenalidomide and dexamethasone compared with lenalidomide and low-dose dexamethasone.

Empliciti in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least one prior course of therapy

• In its summary assessment, the G-BA concludes that, for elotuzumab in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least one prior course of therapy, there is a hint of a minor additional benefit compared with lenalidomide in combination with dexamethasone.
• The G-BA classifies the extent of the additional benefit of elotuzumab in combination with lenalidomide and dexamethasone, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a previously unachieved moderate—and not merely minor—improvement in treatment-related benefit, achieved in particular through a moderate advantage in terms of overall survival.
• Mortality – Overall survival (OS)
  • For the endpoint of overall survival (HR: 0.77, 95% CI [0.61; 0.97], p = 0.0257), elotuzumab in combination with lenalidomide and dexamethasone showed a statistically significant advantage over lenalidomide in combination with dexamethasone.
  • The median survival time in the intervention group was 43.66 months (95% CI: 40.34; n.a.) and is thus 4.1 months longer than in the control group (39.56 months (95% CI: 33.25; n.a.).
  • Subgroup analyses provide proof of an effect modification for the ECOG PS: these show a statistically significant advantage for the patient population with ECOG PS 2 (HR: 0.43, 95% CI [0.23; 0.81], p = 0.007), whereas the analysis of the patient population with ECOG PS 0–1 showed no statistically significant difference (HR: 0.86, 95% CI [0.67; 1.10], p = 0.229).
  • This suggests that the effects of elotuzumab in combination with lenalidomide and dexamethasone are more likely to be observed in patients with a higher disease severity.
  • However, the statistical power of the subgroup results is generally considered too minor to justify an assessment of the additional benefit stratified by ECOG PS, particularly as this effect modification is not observed for the other endpoints.
  • Overall, with regard to all-cause mortality, there is an advantage of elotuzumab in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone for the overall population, which is particularly evident in patients with an ECOG PS of 2.
  • The prolongation in survival achieved is considered to be clinically relevant and more than just a minor improvement.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival, defined as the period between the date of randomisation and the date of the first documented progression or death from any cause, was a co-primary endpoint of the study.
  • At the time of the first data cut-off (29 October 2014), the median progression-free survival was 18.50 weeks in the intervention group versus 14.32 weeks in the control group (HR = 0.68; 95% CI [0.56; 0.83]; p = 0.0001), representing an advantage of 4.2 months in favour of the intervention (elotuzumab in combination with lenalidomide and dexamethasone) with regard to these endpoints.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component ‘disease progression’ was assessed in accordance with the operationalisation based on EBMT criteria and was therefore not symptom-based but determined using laboratory parameter procedures.
  • 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 additional benefit remains unaffected by this.
• Morbidity – disease-related pain according to the BPI-SF, disease-related symptoms according to the EORTC QLQ-C30 and EORTC QLQ-MY20
  • No significant difference was found for the endpoints ‘disease-related pain’ as measured by the BPI-SF, ‘disease-related symptoms’ as measured by the EORTC QLQ-C30, or ‘disease-related symptoms’ as measured by the EORTC QLQ-MY20.
  • The additional benefit for these endpoints is therefore not proven.
• Quality of life – EORTC QLQ-C30 and EORTC QLQ-MY20
  • No significant difference was found for health-related quality of life as measured by the EORTC QLQ-C30 or the EORTC QLQ-MY20.
  • The additional benefit is therefore not proven for the category of health-related quality of life.
• Side effects – serious AEs (SAEs)
  • No statistically significant difference was observed between the treatment groups for the SAE endpoint.
• Overall assessment
  • In the overall assessment of the results, an advantage of elotuzumab in combination with lenalidomide and dexamethasone in terms of overall survival, particularly in patients with a more severe disease, is offset by a disadvantage in the side effects category for the endpoint of severe AEs (CTCAE Grade 3 or 4).
  • The survival benefit of elotuzumab in combination with lenalidomide and dexamethasone compared with lenalidomide in combination with dexamethasone is considered relevant, even against the background of an increased incidence of severe AE of CTCAE Grade 3 or 4.
  • Overall, the negative effects do not therefore call into question the positive effects on the overall survival endpoint.
• Conclusion
  • In its summary assessment, the G-BA concludes that, for elotuzumab in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least one prior line of therapy, there is a hint of a minor additional benefit compared with lenalidomide in combination with dexamethasone.

Courtesy translation only, please refer to the German original.