Brentuximab Vedotin (1) – Adcetris®

• Clinical trials
  • The results of the marketing authorisation study SG035-0003 are available to address the question regarding the extent of the additional benefit. This study is a single-arm, multicentre, open-label Phase II trial.
  • The results of the registration trial SG035-0004 are available to address the question regarding the extent of the additional benefit. This trial is a single-arm, multicentre, open-label Phase II trial.

a) Treatment of relapsed/refractory CD30+ Hodgkin’s lymphoma following autologous stem cell transplantation

• In summary, the extent of the additional benefit of brentuximab vedotin is assessed as follows:
• For adult patients with relapsed or refractory CD30+ Hodgkin’s lymphoma who have received at least one ASCT as prior treatment for their condition, there is an additional benefit, but it is non-quantifiable because the available scientific data do not currently permit this.
• The G-BA classifies the extent of the non-quantifiable additional benefit of brentuximab vedotin on the basis of 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. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• In the present case and indication, the lack of a control group in study SG035-0003 and the lack of validity of the historical controls submitted are relevant to the decision.
• mortality
  • In study SG035-0003, the endpoint ‘overall survival’ was assessed as a secondary endpoint.
  • At the time of the primary analysis (16 September 2010), 13 of the 102 patients had died. The median overall survival, estimated using the Kaplan-Meier method, had not been reached within the observation period.
  • At the time of the second analysis, 36 patients had died; the Kaplan-Meier estimate for median overall survival at that time was 27 months (95% CI: 23.9, --).
  • By the third analysis date (2 April 2012), 40 patients had died; the Kaplan-Meier estimate for median survival had not been reached at the time of this analysis (95% CI: 27; --).
  • Taking all these aspects into account, the extent of the additional benefit of brentuximab vedotin for the endpoint of overall survival cannot be quantified on the basis of the available data, owing to the methodological limitations of the historical control, the uncertainty of the data, and the heterogeneity and inconsistency of the overall survival data from the historical control, the extent of the added benefit of brentuximab vedotin for the endpoint of overall survival is non-quantifiable on the basis of the available data.
• Morbidity – Complete remission (CR)
  • A complete remission associated with a noticeable reduction in disease symptoms for the patient is clinically relevant.
  • 35 patients in the SG035-0003 study achieved complete remission (34%; 95% CI: 25.2; 44.4).
  • Overall, therefore, no conclusion can be drawn regarding the quantification of the patient-relevant additional benefit on the basis of the CR endpoint.
• Morbidity – rate of reduction in B-symptoms
  • The endpoint ‘rate of reduction in B-symptoms’ was defined as the proportion of patients with lymphoma-associated B-symptoms (fever, night sweats, weight loss > 10%) at baseline who achieved a resolution of all B-symptoms at any time during the treatment period.
  • 35 patients (35% of the study population) had detectable lymphoma-associated B-symptoms at the start of the study. 27 patients (77%) achieved a reduction in all B-symptoms.
  • Although there is an additional benefit with regard to the symptoms of fever, night sweats and weight loss, the extent of this benefit cannot be validly quantified, particularly due to a lack of data on the duration of the therapeutic response and the intensity of the symptoms.
• Morbidity – Progression-free survival (PFS), event-free survival (EFS)
  • The median progression-free survival was 25.1 weeks (95% CI: 21.9; 39.1), whilst event-free survival was 29 weeks (95% CI: 23.9; 38.3).
  • Overall, therefore, no conclusion can be drawn regarding the quantification of the patient-relevant additional benefit on the basis of the PFS and EFS endpoints.
• Morbidity – Objective Response Rate (ORR)
  • The ‘objective response rate’ (ORR) was the primary endpoint of the SG035-0003 study.
  • This endpoint was not considered for the present assessment, as no patient-relevant operationalisation was used and this endpoint was assessed exclusively by means of imaging procedures.
• quality of life
  • Quality of life was not assessed in the SG035-0003 study. Consequently, no data are available to assess the additional benefit of brentuximab vedotin in terms of quality of life.
• Side effects
  • The positive effects of brentuximab vedotin are offset by adverse events.
  • In the SG035-0003 study, 98 per cent of patients experienced at least one adverse event, and a quarter of patients were affected by at least one serious adverse event.
  • 20 per cent of patients discontinued treatment with brentuximab vedotin due to adverse events.
  • The most common adverse events were peripheral neuropathies (SMQ ‘peripheral neuropathies’, 55 per cent), particularly sensory neuropathies (47 per cent), as well as fatigue (46 per cent), nausea (42 per cent), upper respiratory tract infections (37 per cent), diarrhoea (36 per cent), pyrexia (29 per cent), vomiting (22 per cent) and neutropenia (22 per cent).
  • Overall, the side effects are classified as significant for patients but, particularly in view of the severity of the disease, are predominantly considered to be manageable and treatable.
  • However, valid conclusions regarding the extent of the additional benefit in relation to adverse events cannot be drawn on the basis of the available data, particularly due to the lack of long-term safety data and the limitation posed by the absence of a control group.
• Overall assessment
  • In its overall assessment of the available results, the G-BA, based on the marketing authorisation and the desired and undesirable effects observed in the aforementioned study, and taking into account the comments received, the oral hearing and the severity of the condition, the G-BA arrives at the following assessment of the extent of the additional benefit: there is an additional benefit, but it is non-quantifiable because the available scientific data do not currently permit this.

b) Treatment of relapsed/refractory CD30+ Hodgkin’s lymphoma following at least two previous lines of therapy, where autologous stem cell transplantation (ASCT) or combination chemotherapy is not a viable treatment option (ASCT-naive patients)

• In summary, the extent of the additional benefit of brentuximab vedotin is assessed as follows:
• For adult patients with relapsed or refractory CD30+ Hodgkin’s lymphoma who have received at least one ASCT as prior treatment for their condition, there is a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of brentuximab vedotin as non-quantifiable on the basis of 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. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• In the present case and indication, the absence of a control group in the submitted studies/case series is particularly relevant to the decision.
• mortality
  • No data on overall survival are available for the aggregated case series of ASCT-naïve patients. It is therefore not possible to draw conclusions regarding the extent of the additional benefit for the patient population of ASCT-naïve patients with regard to the endpoint of overall survival.
• Morbidity – Objective Response Rate (ORR)
  • This is a composite endpoint comprising the sum of the two endpoint categories ‘proportion of patients in partial remission’ and ‘proportion of patients in complete remission’.
  • This endpoint was not included in the present assessment, as no patient-relevant operationalisation was used and this endpoint was assessed exclusively by means of imaging procedures.
• Morbidity – Complete Remission (CR)
  • Complete remission, combined with a reduction in disease symptoms that is noticeable to the patient, is patient-relevant.
  • Of the 41 patients treated in accordance with the marketing authorisation, 22% achieved complete remission.
  • Overall, therefore, due to a lack of information on the assessment and operationalisation of the CR endpoint, no valid statement can be made regarding the quantification of the patient-relevant additional benefit.
• Morbidity – Proportion of patients who underwent a stem cell transplant following treatment with brentuximab vedotin
  • Of the 41 patients who received treatment with brentuximab vedotin for their relapsed/refractory disease in accordance with the marketing authorisation, 8 patients (19%) underwent an ASCT following treatment with brentuximab vedotin.
  • Consequently, no valid conclusion regarding the quantification of the patient-relevant additional benefit can be drawn on the basis of this patient-relevant endpoint.
• quality of life
  • Quality of life was not assessed for the aggregated case series of ASCT-naïve patients. Consequently, no data are available to evaluate the additional benefit in terms of quality of life for this patient population either.
• Side effects
  • Descriptive data on the most common adverse events were presented from the relevant original studies and case series.
  • Adverse events (AEs) with a CTCAE grade of ≥ 3 occurred in 42.4 % of patients. A serious adverse event was observed in 15 patients (25 %). In 7 patients (12 %), adverse events led to therapy discontinuation.
  • In the population of ASCT-naïve patients, too, peripheral neuropathies predominated (SMQ ‘peripheral neuropathy’; 25 patients, 42%).
  • However, valid conclusions regarding the extent of the additional benefit in terms of adverse events cannot be drawn from the available data due to a lack of information on the recording of side effects, the frequency of adverse events, the lack of long-term safety data, the minor number of patients and the limitation posed by the absence of a control group.
• Overall assessment
  • In its overall assessment of the available results, the G-BA, based on the marketing authorisation and the desired and adverse effects observed in the aforementioned studies/case series, and taking into account the comments received, the oral hearing and the severity of the condition, the G-BA arrives at the following assessment of the extent of the additional benefit: there is an additional benefit, but it is non-quantifiable because the current scientific evidence does not permit this at this stage.

c) Treatment of relapsed/refractory systemic anaplastic large cell lymphoma

• In summary, the extent of the additional benefit of brentuximab vedotin is assessed as follows:
• For adult patients with relapsed or refractory CD30+ Hodgkin’s lymphoma who have received at least one ASCT as prior treatment for their condition, there is a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of brentuximab vedotin as non-quantifiable on the basis of 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. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• In the present case and indication, the lack of a control group in the submitted study SG035-0004 and the lack of validity of the submitted historical control are relevant to the decision.
• mortality
  • In study SG035-0004, the endpoint ‘overall survival’ was assessed as a secondary endpoint.
  • At the time of analysis, 19 of the 58 patients had died. The median overall survival, estimated using the Kaplan–Meier method, was not reached within the observation period.
  • The estimated overall survival at 12 months was 70% (95% CI: 59; 82).
  • It is not possible to assess the extent of the additional benefit of brentuximab vedotin with regard to the patient-relevant endpoint ‘overall survival’ due to the uncertainty of the data.
• Morbidity – Complete remission (CR)
  • Complete remission, associated with a reduction in disease symptoms that is noticeable to the patient, is patient-relevant.
  • 59% of patients in the SG035-0004 study achieved complete remission (95% CI: 45; 71).
  • Overall, therefore, no valid conclusion can be drawn regarding the quantification of the extent of the patient-relevant additional benefit on the basis of the CR endpoint.
• Morbidity – rate of reduction in B-symptoms
  • The endpoint ‘rate of reduction in B-symptoms’ was defined as the proportion of patients with lymphoma-associated B-symptoms (fever, night sweats, weight loss > 10%) at baseline who achieved a resolution of all B-symptoms at any time during the treatment period.
  • 17 patients had detectable lymphoma-associated B-symptoms at the start of the study. Of these 17 patients, 14 (82%) achieved a reduction in all B-symptoms.
  • With regard to the symptoms of fever, night sweats and weight loss, there is an additional benefit; however, this is non-quantifiable, particularly due to a lack of data on the duration of the response and the severity of the symptoms.
• Morbidity – Progression-free survival, event-free survival
  • The median progression-free survival, estimated using the Kaplan-Meier method, was 14.3 months (95% CI: 6.9; --), whilst event-free survival was 6.7 months (95% CI: 4.2; 9.5).
  • Overall, therefore, no conclusion can be drawn regarding the quantification of the patient-relevant additional benefit on the basis of the PFS and EFS endpoints.
• Morbidity – Objective Response Rate (ORR)
  • The ‘objective response rate’ (ORR) was the primary endpoint of the SG035-0004 study.
  • This endpoint was not used for the present assessment, as no patient-relevant operationalisation was employed and this endpoint was assessed exclusively by means of imaging procedures.
• quality of life
  • Quality of life was not assessed in the SG035-0004 study. Consequently, no data are available to assess the additional benefit of brentuximab vedotin in terms of quality of life.
• Side effects
  • The positive effects of brentuximab vedotin are offset by adverse events.
  • In the SG035-0004 study, all patients (100 per cent) experienced at least one adverse event. 62 per cent of patients experienced an adverse event of CTCAE grade ≥ 3. 28 per cent of patients discontinued treatment with brentuximab vedotin due to adverse events.
  • The most common adverse events in this population were peripheral neuropathies (SMQ ‘peripheral neuropathies’, 57 per cent), particularly sensory neuropathies (41 per cent), as well as nausea (40 per cent), fatigue (38 per cent), pyrexia (34 per cent), diarrhoea (29 per cent), neutropenia (21 per cent) and upper respiratory tract infections (19 per cent).
  • Overall, the side effects are considered significant for patients but, particularly in view of the severity of the disease and the lack of treatment options, are predominantly classified as manageable and treatable.
  • However, valid conclusions regarding the extent of the additional benefit in relation to adverse events cannot be drawn from the available data due to a lack of information on the frequency of adverse events, the lack of long-term safety data, the minor number of patients and the limitation posed by the absence of a control group.
• Overall assessment
  • In its overall assessment of the available results, the G-BA, based on the marketing authorisation and the desired and adverse effects observed in the aforementioned studies/case series, and taking into account the comments received, the oral hearing and the severity of the condition, the G-BA arrives at the following assessment of the extent of the additional benefit: there is an additional benefit, but it is non-quantifiable because the available scientific evidence does not currently permit this.

Courtesy translation only, please refer to the German original.