Nivolumab (8) – Opdivo®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the randomised, double-blind, actively controlled, three-arm parallel-group trial CA209-067 for the benefit assessment.
  • Relevant to the present assessment are the nivolumab/ipilimumab arm and the nivolumab arm of the aforementioned study.

1b) Previously untreated patients with a BRAF V600 wild-type tumour

• No additional benefit of nivolumab in combination with ipilimumab for the treatment of patients with advanced (unresectable or metastatic) melanoma has been demonstrated for the patient population of previously untreated patients with a BRAF V600There is no proof that the wild-type tumour is superior to the appropriate comparator therapy, nivolumab.
• The findings regarding the certainty of the evidence are justified by the high potential for bias at the endpoint level, the lack of time-to-event analyses regarding disease symptoms and health-related quality of life, and the inadequate evaluation of data on specific adverse events:
• Against this background, the G-BA concludes, upon an overall assessment of the situation, that the additional benefit of nivolumab in combination with ipilimumab is not proven compared with the appropriate comparator therapy.
• mortality
  • Overall survival (OS) is defined as the period between the date of randomisation and the date of death from any cause.
  • For the endpoint of overall survival, no statistically significant difference was observed between the treatment groups for either the 28-month data cut-off or the 36-month data cut-off.
  • 28-month data cut-off: HR: 0.94 [0.71; 1.24]; p = 0.640
  • 36-month data cut-off: HR: 0.90 [0.69; 1.18]; p = 0.442
  • For the endpoint of overall survival, the available data did not demonstrate any additional benefit of nivolumab/ipilimumab compared with nivolumab.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was defined as the period between the date of randomisation and the date of the first documented progression according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) or the date of death from any cause, whichever occurred first.
  • For progression-free survival, no statistically significant difference was observed between the treatment groups at either the 28-month or 36-month data cut-off points.
• Morbidity – symptom scales (EORTC QLQ-C30)
  • No statistically significant difference was observed between the treatment groups for the pain, insomnia and constipation scales.
  • For the scales measuring fatigue, nausea and vomiting, dyspnoea, loss of appetite and diarrhoea, a statistically significant difference was observed in each case to the detriment of nivolumab/ipilimumab compared with nivolumab.
  • Based on the available results for the diarrhoea symptom scale of the EORTC-QLQ-C30 questionnaire, less benefit of nivolumab/ipilimumab compared with nivolumab can be observed in the morbidity endpoint category.
• Morbidity – Health status (EQ-5D VAS)
  • For health status as measured by the EQ-5D VAS, there is a statistically significant difference to the detriment of nivolumab/ipilimumab compared with nivolumab.
• Health-related quality of life – functional scales (EORTC QLQ-C30)
  • For the scales measuring overall health status, physical functioning, role functioning, emotional functioning and social functioning, a statistically significant difference was observed to the detriment of nivolumab/ipilimumab compared with nivolumab.
  • For the quality of life endpoint category, no additional benefit of nivolumab/ipilimumab compared with nivolumab can be inferred from the available data.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, there was a statistically significant difference to the detriment of nivolumab/ipilimumab compared with nivolumab (HR: 2.93 [2.24; 3.82]; p < 0.001).
  • Under nivolumab, a SAE occurred at a median of 19.4 months later than under nivolumab/ipilimumab.
• Side effects – severe adverse events (CTCAE Grade 3–4)
  • For the endpoint of severe AEs (CTCAE Grade 3–4), there was a statistically significant difference to the detriment of nivolumab/ipilimumab compared with nivolumab (HR: 2.36 [1.86; 2.99]; p < 0.001).
  • Under nivolumab, severe AEs (CTCAE Grade 3–4) occurred at a median of 8.6 months later than under nivolumab/ipilimumab.
• Side effects – therapy discontinuation due to adverse events
  • For the endpoint of discontinuation due to AE, there was a statistically significant difference to the detriment of nivolumab/ipilimumab compared with nivolumab monotherapy (RR: 3.25 [2.24; 4.71]; p < 0.001).
• Conclusion on side effects
  • Based on the negative results regarding SUEs, severe AEs (CTCAE Grade 3–4) and therapy discontinuation due to AEs, there is less benefit of nivolumab/ipilimumab compared with nivolumab in the side effects endpoint category.
• Overall assessment
  • Taking into account all the data made available during the benefit assessment procedure, in particular by the pharmaceutical manufacturer, the G-BA initially identifies exclusively negative effects for the combination of nivolumab and ipilimumab.
  • A major disadvantage can be identified in particular for the endpoints of serious AEs and severe AEs (CTCAE Grade 3–4), as well as treatment discontinuation due to AEs.
  • Overall survival was not prolonged, and immune-mediated diarrhoea leads to significant disadvantages in terms of disease symptoms.
  • On the basis of the available data, no therapeutic added value can be inferred for the combination therapy of nivolumab and ipilimumab compared with monotherapy with nivolumab.
  • Against this background, it would be justified to conclude that there is a hint of less benefit for nivolumab in combination with ipilimumab compared with nivolumab (monotherapy).

Courtesy translation only, please refer to the German original.