Brentuximab Vedotin (6) – Adcetris®

• Clinical trials
  • In the trial, brentuximab vedotin in combination with cyclophosphamide, doxorubicin and prednisone (A+CHP) was compared with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

Adults with previously untreated systemic anaplastic large cell lymphoma (sALCL)

• Hint for a minor additional benefit
• Consequently, the G-BA concludes that brentuximab vedotin in combination with CHP offers a minor additional benefit compared with CHOP in the treatment of adults with previously untreated systemic anaplastic large cell lymphoma (sALCL).
• mortality
  • In the ECHELON-2 study, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, the pre-specified stratified analysis shows no statistically significant difference between the treatment arms.
  • The up-coding rule is not applied to the overall survival endpoint.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival is defined as the time from randomisation to the first documented progression, death from any cause, or receipt of subsequent antineoplastic therapy to treat residual lymphoma.
  • There is a statistically significant advantage in the PFS endpoint in favour of A + CHP.
  • The current operationalisation of the PFS endpoint is not suitable for reflecting the failure of a potential cure.
  • The assessment of the morbidity component ‘progression’ was not based on symptoms, but exclusively on imaging procedures (radiologically determined disease progression according to the Cheson criteria). Consequently, the assessment of response is based on asymptomatic findings and is considered not to be directly relevant to patients.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint.
• Morbidity – Recurrence-Free Survival (RFS)
  • The post hoc defined endpoint Recurrence-Free Survival (RFS) is defined as the time from the end of treatment (EoT) until the occurrence of a recurrence or until death from any cause in adults who had achieved CR at the end of treatment.
  • The event-time analysis shows no statistically significant difference between the treatment arms for the RFS endpoint.
  • Furthermore, given that relapses were assessed by local trial staff, it is unclear to what extent the recording and assessment of relapses after the first data cut-off point were comprehensive, complete and consistent.
  • For the reasons stated, there are significant uncertainties in the interpretation of the results for the RFS endpoint; consequently, these are not used in the present assessment to quantify the extent of the additional benefit.
• Morbidity – Event-Free Survival (EFS)
  • In the dossier, the pharmaceutical manufacturer presents analyses of the post hoc defined endpoint EFS, which is defined as the time from randomisation until: disease progression; end of treatment without achieving a complete CR; relapse following CR at the end of treatment; or death from any cause.
  • For brentuximab vedotin in combination with CHP, there is a statistically significant advantage over CHOP for the EFS endpoint.
  • The most common event was ‘progression/relapse’, occurring in 22 % (brentuximab vedotin + CHP) and 31% (CHOP) of patients, respectively, followed by the event ‘no CR at EoT’ in 19% and 21% of patients, respectively.
  • There are uncertainties regarding the interpretation of the effect. Firstly, as relapses were assessed by the local trial staff, it is unclear to what extent, how comprehensively and how consistently the recording and assessment of relapses continued after the first data cut-off.
  • Despite the uncertainties described above regarding the validity of the EFS endpoint, the positive effect of brentuximab vedotin is considered a relevant result for the present assessment, particularly in view of the magnitude of the effect.
• Conclusion on morbidity
  • In the overall assessment of the morbidity endpoints considered for this evaluation, a statistically significant difference in favour of brentuximab vedotin in combination with CHP is evident for the EFS endpoint.
  • For the CR endpoint in patients with B-symptoms at the start of treatment, there is no statistically significant difference between the treatment arms.
  • Overall, therefore, an advantage can be observed for brentuximab vedotin in combination with CHP compared with CHOP.
• Quality of life – functional scales (EORTC QLQ-C30)
  • Health-related quality of life was assessed in the ECHELON-2 study using the functional scales of the disease-specific EORTC QLQ-C30 questionnaire.
  • Based on the difference in mean scores at the end of treatment (EoT), there is no statistically significant difference between the treatment arms.
• Overall assessment
  • For the reassessment of the additional benefit of brentuximab vedotin in combination with cyclophosphamide, doxorubicin and prednisone (CHP) for the treatment of adults with previously untreated systemic anaplastic large cell lymphoma (sALCL), the results of the ECHELON-2 study on the endpoint categories of mortality, morbidity, quality of life and side effects.
  • No statistically significant difference in overall survival was observed between the treatment arms.
  • In the morbidity endpoint category, there is a significant advantage for brentuximab vedotin in combination with CHP compared with CHOP in terms of the event-free survival (EFS) endpoint.
  • For the endpoint of complete remission (CR) in patients with B-symptoms at the start of treatment, there is no statistically significant difference between the treatment arms.
  • Furthermore, there were no statistically significant differences between the treatment arms for health status, symptomatic endpoints or neurological symptoms.
  • There are no statistically significant differences between the treatment arms for the functional scales of the EORTC QLQ-C30 questionnaire. Consequently, no advantage or disadvantage can be identified for brentuximab vedotin in combination with CHP compared with CHOP in terms of health-related quality of life.
  • With regard to side effects, there are also no advantages or disadvantages of brentuximab vedotin in combination with CHP compared with CHOP.
  • An overall review of the available results on patient-relevant endpoints reveals a relevant advantage in terms of morbidity, although this is subject to uncertainty.

Courtesy translation only, please refer to the German original.