Ipilimumab (1) – Yervoy®

Advanced (unresectable or metastatic) melanoma in adults who have previously received treatment

• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’.
• For patients with advanced (unresectable or metastatic) melanoma who have previously received treatment, there is an indication of considerable additional benefit from ipilimumab compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of ipilimumab for patients with advanced (unresectable or metastatic) melanoma who have previously received treatment as ‘considerable’, based on the criteria set out in Section 5(7) of the AM-Nutzen V.
• In light of these considerations, based on the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA concludes that ipilimumab offers considerable additional benefit compared with the appropriate comparator therapy.
• mortality
  • Compared with the appropriate comparator therapy, ‘best supportive care’, the endpoint ‘overall survival’ represents a significant improvement in treatment-related benefit that has not been achieved to date, as a moderate prolongation of survival is achieved.
• morbidity
  • No patient-relevant data on morbidity were collected as separate endpoints.
  • An additional benefit is not proven for morbidity endpoints.
  • As the data submitted by the pharmaceutical manufacturer in the dossier under the heading of morbidity relate to side effects, they were assessed in this context.
• Health-related quality of life
  • Among the individual criteria considered with regard to quality of life (general health status, functional status, symptoms), a statistically significant difference between the treatment groups was observed only for the symptom ‘constipation’, to the detriment of the ipilimumab/BSC group.
  • As no further statistically significant differences between the patient populations could be demonstrated, no general advantage or disadvantage of ipilimumab can be inferred from this result with regard to the patient-relevant endpoint ‘health-related quality of life’.
  • The response rate for the questionnaires at the 12-week follow-up visit was approximately 80% for patients still alive at that time.
  • Furthermore, quality-of-life data were also collected at the 24-week follow-up; however, these were not usable due to the low response rate.
  • An additional benefit or a less benefit for the endpoint ‘health-related quality of life’ is therefore not proven.
• Side effects
  • There is no evidence of greater or minor harm from ipilimumab in combination with best supportive care compared with best supportive care alone, as measured by the overall rates of adverse events, severe (CTCAE grade ≥ 3) and serious adverse events.
  • The difference between the groups was not statistically significant.
  • However, with regard to immune-mediated adverse events, there are indications of greater harm associated with ipilimumab due to immune-mediated adverse events, both severe and serious immune-mediated adverse events, as well as therapy discontinuations due to immune-mediated adverse events.
  • A statistically significant result is available for each of the four endpoints.
  • The severity of the immune-mediated adverse events is not considered to be such that a downgrading is warranted when weighing up the extent of the additional benefit.
  • The summary of product characteristics (SmPC) for ipilimumab sets out specific guidelines on how to proceed in the event of immune-mediated adverse events, enabling the majority of these side effects to be successfully treated.
  • The findings regarding side effects therefore do not, in this case, lead to a change in the overall assessment of the extent of the additional benefit.
• Overall assessment
  • When the results on mortality, quality of life and side effects are considered as a whole, there is no sustained, previously unachieved significant improvement in treatment-related benefit compared with the appropriate comparator therapy, in particular, no cure, no major prolongation of survival, and no long-term freedom from serious symptoms.
  • Therefore, a classification as ‘major additional benefit’ would not be justified.
  • The findings on survival duration, when considered alongside the data on quality of life and side effects, are assessed as a clear improvement in benefit not previously achieved compared with the appropriate comparator therapy, and in particular as a moderate prolongation of survival duration.

Courtesy translation only, please refer to the German original.