Ipilimumab (4) – Yervoy®

• Clinical trials
  • For the purpose of the benefit assessment, the pharmaceutical manufacturer submitted data from the randomised, double-blind, actively controlled, three-arm parallel-group trial CA209-067, the open-label, active-controlled Phase I trial CA209-038, and the randomised, controlled trial CA209-170.
  • Relevant to the present assessment are the ipilimumab/nivolumab arm and the nivolumab arm of study CA209-067.
  • Also relevant to this assessment are the results of study arms three and four of the open-label, actively controlled Phase I study CA209-038, in which the combination of ipilimumab and nivolumab was compared with nivolumab monotherapy in each case.

a) Ipilimumab in combination with nivolumab for the treatment of previously untreated adult patients with advanced (unresectable or metastatic) melanoma harbouring a BRAF V600 mutation

• For previously untreated patients with a BRAF V600-mutated tumour, the additional benefit of ipilimumab in combination with nivolumab compared with the appropriate comparator therapy is not proven, as the pharmaceutical manufacturer has not submitted a head-to-head comparative study that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.
• The matching-adjusted indirect comparison submitted cannot be taken into account solely on the grounds that the search for studies on the appropriate comparator therapy was incomplete and unsystematic.
• Furthermore, for none of the reported endpoints was a difference between the treatment groups observed that was of an extent that, despite the methodological limitations, would have allowed an assessment of the additional benefit.

b) Ipilimumab in combination with nivolumab for the treatment of previously untreated adult patients with advanced (unresectable or metastatic) melanoma with BRAF V600 wild-type

• Rather, the G-BA follows the IQWiG’s assessment findings from dossier evaluation 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]).
  • With regard to the subgroup characteristic of PD-L1 status, none of the analyses of overall survival revealed a statistically significant interaction (p-value > 0.05) between the patient populations, regardless of the threshold considered (< 1% vs. ≥ 1%, < 5% vs. ≥ 5% and < 10% vs. ≥ 10%), and regardless of whether the overall population of the CA209-067 study or the patient population under evaluation with BRAF V600 wild-type was considered.
  • For the endpoint of overall survival, the available data do not provide proof of an additional benefit of ipilimumab in combination with nivolumab compared with nivolumab alone.
• 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, no statistically significant difference was observed between the treatment groups at the 36-month data cut-off (HR: 0.86 [95% CI: 0.67; 1.10]; p-value 0.243).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• Morbidity – EORTC-QLQ-C30
  • Symptoms of the disease were recorded only in study CA209-067 using the eight symptom scales of the validated EORTC-QLQ-C30 questionnaire.
  • For the benefit assessment, event time analyses (time to confirmed deterioration) based on a MID of 10 points were used; a statistically significant difference between the interventions was observed solely for the constipation symptom scale (16% vs. 9.7%, HR: 1.82 [95% CI: 1.06; 3.14], p-value 0.031).
• 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 ipilimumab in combination with nivolumab (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 ipilimumab in combination with nivolumab compared with nivolumab alone (HR: 2.95 [2.28; 3.81]; p: not available).
  • In the CA209-067 study, a SAE occurred at a median of 19.4 months later with nivolumab alone than with ipilimumab in combination with nivolumab.
• 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 ipilimumab in combination with nivolumab compared with nivolumab alone (HR: 2.37 [1.88; 2.99]; p-value not available).
  • In the CA209-067 study, a severe AE (CTCAE Grade 3–4) occurred at a median of 8.6 months later with nivolumab alone than with ipilimumab in combination with nivolumab.
• Side effects – discontinuation due to adverse events
  • For the endpoint of discontinuation due to AEs, there was a statistically significant difference to the detriment of ipilimumab in combination with nivolumab compared with nivolumab alone (HR: 4.12 [95% CI: 2.78; 6.10]; p-value not available).
• Overall assessment
  • 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.
  • For the patient population relevant to the assessment – treatment-naive patients with advanced BRAF V600 wild-type melanoma – major disadvantages can be identified, particularly for the endpoints of serious AEs (CTCAE Grade 3–4) and severe AEs (CTCAE Grade 3–4), as well as discontinuation due to AEs.
  • Furthermore, statistically significant differences to the detriment of ipilimumab in combination with nivolumab are evident on the ‘constipation’ scale of the EORTC-QLQ-C30 questionnaire, in the ‘morbidity’ endpoint category, as well as in the ‘cognitive functioning’ scale within the ‘quality of life’ endpoint category.
  • On the basis of the available data, therefore, no therapeutic benefit of the combination therapy of nivolumab and ipilimumab can be inferred compared with nivolumab monotherapy.
  • 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.

c) Ipilimumab in combination with nivolumab for the treatment of previously treated adult patients with advanced (unresectable or metastatic) melanoma

• For previously treated patients, the additional benefit of ipilimumab in combination with nivolumab compared with the appropriate comparator therapy is not proven, as the pharmaceutical manufacturer has not submitted any study that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.