Nivolumab (10) – Opdivo®

• Clinical trials
  • The nivolumab/ipilimumab arm and the nivolumab arm of the CA209-067 trial are relevant to this assessment.
  • Also relevant to this assessment are the results of parts three and four of the open-label, actively controlled Phase I trial CA209-038, in which the combination of ipilimumab and nivolumab was compared with nivolumab monotherapy in each case.

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

• Rather, the G-BA follows the IQWiG’s assessment findings from dossier assessment A18-40 of 13 September 2018 and, in accordance with Section 5(7)( 6 of the AM-NutzenV, that the benefit of combination therapy with nivolumab and ipilimumab for previously untreated patients with advanced (unresectable or metastatic) melanoma with a BRAF V600wild-type tumour is less than the benefit of monotherapy with nivolumab.
• mortality
  • Overall survival (OS) was defined in both studies included as the time from randomisation to death from any cause.
  • The meta-analysis of the event-time analyses for both studies revealed no statistically significant difference (HR: 0.86 [95% CI: 0.67; 1.11]).
  • Based on the available data, the additional benefit of nivolumab in combination with ipilimumab compared with nivolumab alone for the endpoint of overall survival is not proven.
• Morbidity – Progression-free survival (PFS)
  • In the CA209-067 study, PFS was defined as the time from randomisation to 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, there was no statistically significant difference between the treatment groups at the 36-month data cut-off (HR: 0.86 [95% CI: 0.67; 1.10]; p-value 0.243).
• Morbidity – EORTC-QLQ-C30
  • Symptoms of the disease were assessed only in study CA209-067 using the eight symptom scales of the validated EORTC-QLQ-C30 questionnaire.
  • Only for the constipation symptom scale (16% vs. 9.7%, HR: 1.82 [95% CI: 1.06; 3.14], p-value 0.031) showed a statistically significant difference between the interventions, to the detriment of nivolumab in combination with ipilimumab.
• Morbidity – EQ-5D Visual Analogue Scale
  • The health status of the study patients in study CA209-067 was assessed using the EQ-5D visual analogue scale.
  • Based on the presented responder analyses, taking into account a MID of 7 or 10 scale points, no statistically significant differences were observed.
• Quality of life – EORTC-QLQ-C30
  • Quality of life was assessed only in study CA209-067 using the symptom scales of the validated EORTC-QLQ-C30 questionnaire.
  • For the cognitive functioning scale, a statistically significant difference was observed to the detriment of nivolumab in combination with ipilimumab (29.6% vs. 23.1%, HR: 1.48 [95% CI: 1.02; 2.15]; p-value 0.039).
• Side effects – Serious adverse events (SAEs)
  • For the SAE endpoint, there was a statistically significant difference to the detriment of nivolumab in combination with ipilimumab compared with nivolumab alone (HR: 2.95 [2.28; 3.81]; p-value not available).
  • In the CA209-067 study, a SAE occurred at a median of 19.4 months later with nivolumab alone than with nivolumab in combination with ipilimumab.
• Side effects – severe AEs (CTCAE Grade 3–4)
  • For the endpoint of severe AEs (CTCAE Grade 3–4), a statistically significant difference was observed to the detriment of nivolumab in combination with ipilimumab compared with nivolumab (HR: 2.37 [1.88; 2.99]; p-value not available).
  • In the CA209-067 study, a severe AE (CTCAE Grade 3–4) occurred, on a median of 8.6 months later, with nivolumab alone than with nivolumab in combination with ipilimumab.
• Side effects – discontinuation due to adverse events
  • For the endpoint of discontinuation due to AE, there was a statistically significant difference to the detriment of nivolumab in combination with ipilimumab compared with nivolumab (HR: 4.12 [95% CI: 2.78; 6.10]; p-value not available).
• Overall assessment / Conclusion
  • Taking into account all the data made available during the benefit assessment process, the G-BA identified exclusively negative effects for the combination of nivolumab and ipilimumab compared with nivolumab alone.
  • For the patient population relevant to the assessment – treatment-naïve patients with advanced BRAF V600 wild-type melanoma – major disadvantages can be identified, particularly with regard to the endpoints of serious AEs (CTCAE Grade 3–4) and severe AEs (CTCAE Grade 3–4), as well as treatment discontinuation due to AEs.
  • On the basis of the available data, therefore, no therapeutic added value can be inferred for the combination therapy of nivolumab and ipilimumab compared with monotherapy with nivolumab.
  • Given the significant potential for adverse effects, coupled with the absence of positive effects, the available data do not support any additional benefit of nivolumab in combination with ipilimumab compared with nivolumab monotherapy in the treatment of treatment-naïve patients with advanced BRAF V600 wild-type melanoma.

Courtesy translation only, please refer to the German original.