Brentuximab Vedotin (2) – Adcetris®

• Clinical trials
  • The pharmaceutical manufacturer has submitted the randomised, double-blind, placebo-controlled registration trial AETHERA to demonstrate the extent of the additional benefit.

a) adult patients with CD30+ Hodgkin’s lymphoma (HL) at increased risk of relapse or progression following an autologous stem cell transplant (ASCT)

• mortality
  • For the endpoint of overall mortality, data are available for the overall population based on the data cut-off of 18 August 2014 and the data cut-off of 14 October 2015.
  • Median survival was not reached in either of the two populations or study arms.
  • Based on the available interim analyses, no significant difference in overall survival between brentuximab vedotin and placebo could be demonstrated, either for the overall population or for patients with ≥ 2 risk factors.
  • The results are potentially biased due to the crossover effect and the limited maturity of the data, and cannot be validly assessed.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was assessed by an independent review committee as the primary endpoint in accordance with the Revised Response Criteria for Malignant Lymphoma and is defined as the time from randomisation to disease progression or death, regardless of the cause of death, whichever occurred first.
  • At the time of the primary analysis, 36% of patients in the brentuximab vedotin arm and 46% of patients in the placebo arm had experienced a PFS event.
  • The risk of a PFS event was reduced by 43% for patients treated with brentuximab vedotin compared with those treated with placebo (hazard ratio (HR): 0.57; 95% CI [0.40; 0.81]; p = 0.0013).
  • At the latest data cut-off on 14 October 2015, the HR was 0.58 for the entire study population and 0.49 for patients with ≥ 2 risk factors.
  • The median PFS was prolonged by 18.4 months in the overall population receiving brentuximab vedotin and by 30.6 months in patients with ≥ 2 risk factors.
  • The endpoints were assessed almost exclusively on the basis of morphological and imaging features, without recording symptoms perceptible to the patient.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint for patients.
• quality of life
  • No suitable data were submitted for the assessment of quality of life.
• Side effects
  • In the AETHERA trial, almost every patient in the brentuximab arm experienced an adverse event (98 per cent). By contrast, adverse events occurred in 89% of the overall population in the placebo arm and in 87% of patients with ≥ 2 risk factors.
  • Serious adverse events (SAEs) and adverse events classified as ‘severe adverse events’ (CTCAE grade ≥ 3) occurred statistically significantly more frequently in patients in the intervention arm receiving brentuximab vedotin (56% and 25%) than in patients in the control group (32% and 13%).
  • A similar pattern was observed in the patient group with ≥ 2 risk factors: for SAE and , statistically significant results were found to the detriment of brentuximab vedotin (SAE: relative risk = 1.76 [95% CI: 1.05; 2.95]; p = 0.03; NCI-CTCAE Grade ≥ 3 AEs: relative risk = 1.63 [1.24; 2.14]; p = 0.0003).
  • Statistically significant results are also available for both patient populations regarding adverse events leading to discontinuation of study medication, with little difference in effect size or direction: for example, treatment discontinuations occurred in 30 per cent of patients in the brentuximab vedotin arm, whereas in the placebo arm, 5% of patients experienced therapy discontinuation (RR = 5.68; 95% CI [2.65; 12.18]; p < 0.0001).
  • Significantly more patients receiving brentuximab vedotin experienced disorders of the nervous system, the blood and the lymphatic system, as well as gastrointestinal disorders.
  • The occurrence of peripheral neuropathies is of particular relevance to patients. The risk of developing peripheral neuropathies is approximately three times higher with brentuximab vedotin (RR = 3.46; 95% CI [2.48; 4.83]; p < 0.00001, overall safety population).
  • Grade 3 peripheral neuropathies were significantly more common with brentuximab.
  • At the time of the final follow-up, neuropathies were reversible in 59% of patients in the intervention arm and 87% of patients in the control arm. However, in the study population, peripheral neuropathies (predominantly grade 1) persisted in 41% of patients receiving Brentuximab Vedotin and 13% of those receiving placebo.
  • When interpreting the results regarding side effects, it should be noted that the duration of treatment differed by approximately 4 weeks between the groups, which could potentially influence the findings on side effects.
• Overall assessment / Conclusion
  • The AETHERA study provides results comparing brentuximab vedotin with placebo regarding mortality (overall survival), morbidity and side effects, which can be used to assess the extent of the additional benefit of brentuximab vedotin.
  • For the endpoint of overall survival, the results show no statistically significant differences between the treatment arms. Due to the high crossover rate, the result for overall survival is potentially highly biased and cannot be validly interpreted.
  • For the endpoint ‘time to allogeneic transplantation’, the median ‘time-to-event’ analysis was not reached; however, a statistically significant reduction in the risk of undergoing a stem cell transplant was observed for patients treated with brentuximab vedotin only in those with ≥ 2 risk factors.
  • Data on quality of life were not collected in this study. Taking into account the course of the disease, its severity and the established treatment approach in this indication (watchful waiting), data on quality of life would have been particularly desirable for assessing the therapeutic value of brentuximab vedotin.
  • An overall review of the side effects reveals statistically significant results to the detriment of the drug under evaluation with regard to severe adverse events (SAEs), adverse events classified as ‘severe adverse events’ (CTCAE grade ≥ 3), therapy discontinuations and, above all, peripheral neuropathies, statistically significant results unfavourable to the medicinal product under evaluation.
  • In particular, the occurrence of these patient-relevant side effects must be weighed up when selecting brentuximab vedotin for the treatment of patients with CD30+ Hodgkin’s lymphoma with an increased risk of relapse or progression following an ASCT, against the background of the lack of demonstrated advantage in overall survival and the absence of quality-of-life data.

Courtesy translation only, please refer to the German original.