Nivolumab (1) – Opdivo®

• Clinical trials
  • The CA209-066 trial is a randomised, double-blind comparative trial in which patients with advanced melanoma with BRAF V600 wild-type were treated with either nivolumab or dacarbazine chemotherapy.
  • Study CA209-037 is a randomised comparative trial that included patients who had already been treated for advanced melanoma. In this two-arm trial, treatment with nivolumab was compared with treatment at the clinician’s discretion.
  • The CA209-067 study is a randomised controlled trial with three treatment arms: nivolumab versus ipilimumab versus nivolumab in combination with ipilimumab.

1) Untreated patients with a BRAF V600-mutated tumour

• For untreated patients with a BRAF V600-mutated tumour, additional benefit is not proven.
• In the absence of a direct comparative study of nivolumab against the appropriate comparator therapy (vemurafenib), the pharmaceutical manufacturer relies on an adjusted indirect comparison to demonstrate additional benefit in the patient group of previously untreated patients with a BRAF V600-mutated tumour.
• However, as the assumption of comparability – a prerequisite for an indirect comparison – cannot be regarded as fulfilled, the indirect comparison presented does not constitute a sufficiently meaningful data basis on which to assess the additional benefit of nivolumab compared with vemurafenib.
• In particular, the studies are not comparable because the results for the endpoints relating to side effects differ significantly between the dacarbazine arms of the two studies: Serious adverse events (SAEs) occurred in significantly more patients in the dacarbazine arm of the CA209-066 study than in the dacarbazine arm of the BRIM3 study: 38% vs. 16%.
• Furthermore, in study CA209-066, significantly more patients in the dacarbazine arm discontinued treatment due to an adverse event than in study BRIM3: 12% vs. 4%.

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

• There is an indication of considerable additional benefit for previously untreated patients with a BRAF V600 wild-type tumour.
• For this patient group, the G-BA classifies the extent of the additional benefit of nivolumab as considerable, based on the criteria 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.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit that has not previously been achieved, particularly as a moderate prolongation of survival is achieved.
• As the results of only one study form the basis of the benefit assessment, the level of certainty regarding the findings allows, at most, indications of an additional benefit to be inferred.
• Consequently, the certainty of the findings regarding the established additional benefit is classified as ‘indication’.
• mortality
  • overall survival
  • Treatment with nivolumab shows a statistically significant prolongation in overall survival compared with treatment with dacarbazine (hazard ratio: 0.42 [0.30; 0.60], p < 0.001).
  • The median survival time has not yet been reached in the nivolumab arm of the study, compared with a median survival time of 10.84 months in the dacarbazine arm of the study.
  • These results on overall survival from the data cut-off date of 1 July 2014 are confirmed in the subsequent data cut-off date of 15 July 2015, although this is only used as supplementary data for the present evaluation (hazard ratio: 0.43 [0.33; 0.57], p < 0.001).
  • With regard to the overall survival results (data cut-off of 1 July 2014), the subgroup analysis suggests an indication of an effect modification based on the patients’ sex.
  • Accordingly, the effect is more pronounced in men than in women.
• morbidity
  • Progression-free survival
  • The median progression-free survival (PFS) was 5.06 months in the nivolumab treatment group compared with 2.17 months in the dacarbazine treatment group.
  • The difference is statistically significant (hazard ratio: 0.43 [0.34; 0.56], p < 0.0001).
  • 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.
  • Symptoms
  • Symptoms were assessed in the study using the cancer-specific EORTC QLQ-C30 questionnaire (symptom scales).
  • However, in the analyses presented, the proportion of patients included in the analysis was, overall, too minor to allow for reliable conclusions to be drawn regarding treatment effects.
  • Consequently, there are no sufficiently robust results available to assess the additional benefit with regard to symptoms.
  • health status
  • Health status was assessed in the study using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • However, the analyses presented do not yield sufficiently reliable results, for the same reasons as those already outlined under ‘Symptoms’.
• quality of life
  • Quality of life was measured in the study using the functional scales of the EORTC QLQ-C30 questionnaire.
  • However, the analyses presented do not yield sufficiently reliable results, for the same reasons as those already outlined under ‘Symptoms’.
• Side effects
  • The analyses of adverse events presented in the dossier also include events attributable to progression of the underlying disease.
  • For the present assessments, the analyses submitted by the pharmaceutical manufacturer in its written statement are used, in which adverse events attributable to progression of the underlying disease were excluded.
  • In the CA209-066 study, a very high overall rate of adverse events was recorded, both in patients treated with nivolumab and in those treated with dacarbazine.
  • With regard to the endpoint ‘adverse events’, no conclusions can be drawn for the assessment of additional benefit in a comparative evaluation.
  • The proportion of patients with at least one serious adverse event (SAE) was lower in the nivolumab treatment group.
  • Furthermore, the time-adjusted analysis of the median time to the first occurrence of a SAE shows a statistically significant advantage for nivolumab.
  • Furthermore, for the endpoints ‘Severe adverse events (CTCAE grades 3 and 4)’ and ‘therapy discontinuation due to adverse events’, the number of patients experiencing such an event was minor in the nivolumab treatment group compared with the dacarbazine treatment group.
  • Furthermore, the time-adjusted analysis for the median time to first occurrence of the event also showed a statistically significant advantage for nivolumab for these endpoints.
• Overall assessment
  • For previously untreated patients with a BRAF V600 wild-type tumour, data on mortality, morbidity and side effects are available for the assessment of the additional benefit of nivolumab compared with the appropriate comparator therapy (dacarbazine or ipilimumab).
  • The overall assessment takes into account the lack of meaningful data on both disease-specific symptoms and patients’ quality of life.
  • The mortality results show that treatment with nivolumab achieves an extension of overall survival compared with dacarbazine, the extent of which is assessed as a moderate prolongation of survival.
  • Overall, a considerable additional benefit of nivolumab over dacarbazine is identified for untreated patients with a BRAF V600 wild-type tumour.

3) Previously treated patients

• An additional benefit is not proven for previously treated patients.
• In summary, the results presented from study CA209-037 are not sufficient to assess the additional benefit of nivolumab over the appropriate comparator therapy – a patient-specific treatment determined by the treating doctor, taking into account the approval status and the respective prior treatment – to assess the added benefit of nivolumab over the appropriate comparator therapy.
• It cannot be assumed that the factor of prior treatment – and thus differences between previously untreated (treatment-naive) and previously treated patients – has no influence on the therapeutic effects of both nivolumab and the respective comparator therapy.
• In summary, it is therefore concluded that the data submitted are not suitable for assessing the additional benefit of nivolumab compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.