Brentuximab Vedotin (5) – Adcetris®

• Clinical trials
  • ECHELON-2 is a multicentre, double-blind, randomised controlled Phase III trial comparing brentuximab vedotin in combination with cyclophosphamide, doxorubicin and prednisone (CHP) with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL)

• In summary, the additional benefit of brentuximab vedotin in combination with cyclophosphamide, doxorubicin and prednisone (CHP) is assessed as follows:
• 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 adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL).
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘hint’.
• mortality
  • overall survival
  • For sALCL patients, treatment with brentuximab vedotin + CHP demonstrates a statistically significant advantage in terms of overall survival compared with treatment with CHOP; this advantage is assessed as a relevant improvement, but of a minor extent.
  • The median survival time at the time of the second data cut-off on 25 September 2019 had not yet been reached in either study arm.
  • At the endpoint level, there is uncertainty regarding the overall survival result, due to the wide confidence interval for the effect estimate, the upper limit of which is 0.99.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the ECHELON-2 study and is defined as the time from randomisation to the first documented event of progression, death from any cause, or receipt of subsequent antineoplastic therapy to treat residual lymphoma (whichever occurs first).
  • PFS was statistically significantly prolonged in the intervention arm compared with the control arm.
  • Consequently, the assessment of response in these areas is based on asymptomatic findings and is considered not to be of direct relevance 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 pharmaceutical manufacturer presents analyses in the dossier regarding the post hoc defined endpoint recurrence-free survival (RFS).
  • In the event-time analysis, which takes into account the timing of recurrence events and deaths, no statistically significant difference between the treatment arms is observed for the RFS endpoint.
  • 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)
  • The pharmaceutical manufacturer presents analyses in the dossier for 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 a 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.
  • Despite the uncertainties described above regarding the interpretability 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.
• Health-related 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 end-of-treatment (EoT), there is no statistically significant difference between the treatment arms.
  • Overall, no advantages or disadvantages for brentuximab vedotin in combination with CHP compared with CHOP can be inferred with regard to health-related quality of life.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants.
  • The results are presented here for supplementary information only.
• Overall assessment / Conclusion
  • With regard to overall survival, there is a statistically significant advantage for brentuximab vedotin + CHP compared with treatment with CHOP; this advantage is considered to be relevant, but of a minor extent.
  • In the morbidity endpoint category, a relevant advantage was observed for brentuximab vedotin in combination with CHP compared with CHOP for the event-free survival (EFS) endpoint.
  • However, the interpretability of the EFS endpoint is subject to uncertainties. Given the magnitude of the effect, the result is nevertheless taken into account for the present assessment.
  • For the other patient-relevant morbidity endpoints, no difference is observed between the treatment arms.
  • No differences were observed between the treatment arms in terms of quality of life and side effects.
  • An overall review of the available results for the patient-relevant endpoints reveals a significant, but in its extent no more than a minor, advantage in terms of overall survival, as well as a significant advantage in terms of morbidity, which is, however, subject to uncertainty.
• Overall assessment / Conclusion
  • For overall survival, there is a statistically significant advantage with brentuximab vedotin + CHP compared with treatment with CHOP, which is assessed as a relevant, though not more than a minor, advantage.
  • In the morbidity endpoint category, a relevant advantage is observed for brentuximab vedotin in combination with CHP compared with CHOP for the event-free survival (EFS) endpoint.
  • However, the interpretability of the EFS endpoint is subject to uncertainty. Given the magnitude of the effect, the result is nevertheless taken into account for the present assessment.
  • For the other patient-relevant morbidity endpoints, no difference is observed between the treatment arms.
  • No differences were observed between the treatment arms with regard to quality of life and side effects.
  • An overall review of the available results for patient-relevant endpoints reveals a significant, but in its extent a minor, advantage in terms of overall survival, as well as a significant advantage in terms of morbidity, although this is subject to uncertainty.

Courtesy translation only, please refer to the German original.