Brentuximab Vedotin (4) – Adcetris®

Adult patients with previously untreated stage IV CD30+ Hodgkin’s lymphoma (HL)

• Consequently, the G-BA classifies the extent of the non-quantifiable additional benefit of brentuximab vedotin as non-quantifiable, based on 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 11, first clause of SGB V, but is non-quantifiable.
• mortality
  • In the ECHELON-1 study, overall survival was defined as the time from randomisation to the patient’s death, regardless of the underlying cause.
  • Treatment with A + AVD resulted in a statistically significant advantage in overall survival compared with ABVD (hazard ratio = 0.52 [0.27; 0.995], p-value = 0.044).
  • Due to the very low number of events occurring in the study arms (3% and 6% respectively), the results for the overall survival endpoint are of limited interpretative value.
• Morbidity – Modified Progression-Free Survival (mPFS) / Treatment Failure
  • The primary endpoint of the ECHELON-1 trial was modified progression-free survival. This was defined as the time from randomisation to the first documented instance of disease progression, death from any cause, or – in patients with an incomplete response – the receipt of subsequent antineoplastic chemotherapy or radiotherapy for HL following the scheduled completion of first-line therapy.
  • A statistically significant difference was observed in favour of A+AVD.
  • Based on the current operationalisation of the mPFS endpoint, it is not possible to draw sufficiently robust conclusions regarding treatment effects in terms of treatment failure and, consequently, the failure of the attempt at a cure.
  • For these reasons, the results for the mPFS endpoint are not taken into account in this evaluation.
• Morbidity – Recurrence-free survival
  • RFS is defined as the time from CR to recurrence or death from any cause in patients with CR.
  • In the event-time analysis, which takes into account the timing of recurrence events and deaths, a statistically significant difference in favour of A+AVD is observed for the RFS endpoint.
  • Due to the breach of randomisation and the other uncertainties described, the results for the RFS endpoint cannot be used to quantify the extent of the additional benefit.
• quality of life
  • The functional scales of the EORTC QLQ-C30 questionnaire were used to assess health-related quality of life.
  • At the time of the end-of-treatment (EoT) visit, statistically significant differences to the detriment of A+AVD were observed in the physical functioning, role functioning and social functioning scales.
  • As the confidence interval for Hedges’ g lies entirely outside the non-significance range for all three scales, the effects are considered clinically relevant.
  • At the 9-month post-EoT time point, there were no statistically significant differences between the study arms for the five scales: general health status/quality of life, physical functioning, role functioning, emotional functioning and social functioning.
• Side effects – Serious adverse events (SAE)
  • For serious adverse events, a statistically significant difference was observed to the detriment of A+AVD.
• Conclusion on side effects
  • An overall review of the results for the ‘side effects’ endpoint category reveals predominantly disadvantages for A+AVD compared with ABVD.
  • Advantages for A+AVD are evident only for the endpoint ‘discontinuation of ≥ 1 component of the study medication due to AEs’ and the SMQ for interstitial lung disease.
  • Due to the use of ABVD in the control arm, which no longer complies with guidelines, and the fact that G-CSF prophylaxis was not administered to the majority of patients, there are uncertainties regarding the interpretation of the results.
• Overall assessment
  • Results from the ECHELON-1 trial are available for the benefit assessment of brentuximab vedotin in combination with doxorubicin, vinblastine and dacarbazine (A+AVD) for the treatment of adult patients with stage IV CD30+ Hodgkin’s lymphoma (HL), the ECHELON-1 trial provides results on mortality, morbidity, quality of life and side effects compared with the ABVD polychemotherapy regimen (doxorubicin, bleomycin, vinblastine and dacarbazine).
  • As the ABVD regimen used in the control arm does not correspond to the German treatment standard BEACOPP-escalated, which is currently regarded as generally accepted, it appears justified to attribute only limited relevance to the results of the ECHELON-1 trial in the German healthcare context.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of A+AVD. However, due to the very small number of events that occurred, the results for the endpoint of overall survival are of limited significance.
  • For the recurrence-free survival endpoint, there is a statistically significant advantage in favour of A+AVD. Owing to the breach of randomisation and other relevant uncertainties, the results for the RFS endpoint cannot be used to quantify the extent of the additional benefit.
  • For the other endpoints in the morbidity category (EQ-5D, EORTC QLQ-C30), there are no statistically significant or clinically relevant differences between the study arms.
  • The data on health-related quality of life show clinically relevant adverse effects during treatment with A+AVD on the physical function, role functioning and social functioning scales. With regard to the period following the completion of treatment with A+AVD and ABVD, there are no effects for which clinical relevance can be inferred with sufficient certainty.
  • The results for the endpoint category ‘side effects’ predominantly show disadvantages of A+AVD compared with ABVD. The interpretation of the results is subject to uncertainty due to the use of ABVD in the control arm, which no longer complies with guidelines, and the fact that G-CSF prophylaxis was not administered to the majority of patients.

Courtesy translation only, please refer to the German original.