Nivolumab (2) – Opdivo®, Nivolumab BMS

• Clinical trials
  • The pharmaceutical manufacturer has based its benefit assessment in the dossier on the results of the CA209-017 trial. This trial is the pivotal registration trial for nivolumab in the indicated therapeutic indication, in which patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with squamous cell tumour histology following prior treatment with platinum-based chemotherapy. The CA209-017 trial investigated the therapeutic effects of nivolumab compared with docetaxel in a randomised, open-label comparison.

1) Patients for whom treatment with docetaxel is indicated

• mortality
  • overall survival
  • Treatment with nivolumab was associated with a statistically significant prolongation of overall survival compared with treatment with docetaxel (hazard ratio: 0.59 [0.44; 0.79], p < 0.001). The median survival time was 9.2 months in the nivolumab group compared with 6.0 months in the docetaxel group, representing a median survival benefit of 3.2 months.
  • These results from the data cut-off date of 15 December 2014 are confirmed in the subsequent data cut-off date of 30 July 2015, which is also used to supplement the present assessment: Hazard ratio: 0.62 [0.47; 0.81], p < 0.001; median survival time 9.2 versus 6.0 months.
  • With regard to the overall survival results (data cut-off date of 15 December 2014), the subgroup analysis provides proof of an effect modification by patient age (< 75 years, ≥ 75 years). This analysis reveals a statistically significant prolongation of survival in the patient population of under 75 years of age, but not in the patient population of over 75 years of age, for whom the patient population analysis shows no statistically significant difference between the treatments.
• morbidity
  • Progression-free survival
  • The median progression-free survival (PFS) was 3.5 months in the nivolumab treatment group compared with 2.8 months in the docetaxel treatment group. The difference is statistically significant (hazard ratio: 0.62 [0.47; 0.81], p < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories. The ‘mortality’ component of the endpoint was assessed in the CA209-017 study via the ‘overall survival’ endpoint as a standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms
  • Disease-related symptoms were assessed in the CA209-017 study using the lung cancer-specific questionnaire ‘Lung Cancer Symptom Scale (LCSS)’. 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 reliable results available to assess the additional benefit with regard to symptoms. Due to the insufficient statistical power, the results are not presented.
  • health status
  • Health status was assessed in the CA209-017 study using the visual analogue scale (VAS) from the EQ-5D questionnaire. However, the analyses presented do not yield sufficiently robust results, as here too the proportion of patients included in the analysis was, overall, too minor to allow for reliable conclusions to be drawn regarding the effects of the treatment.
• quality of life
  • Health-related quality of life was also assessed in the CA209-017 study using the lung cancer-specific questionnaire ‘Lung Cancer Symptom Scale (LCSS)’.
  • Consequently, there are no sufficiently reliable results available to assess the additional benefit in terms of quality of life. Due to the insufficient statistical power, the results are not presented here.
• Side effects
  • Comments on the available analyses:
  • The analyses of adverse events presented in the dossier also include events attributable to progression of the underlying disease, e.g. events with thepreferred term (PT according to MedDRA): ‘Malignant lung neoplasm’ or ‘Bone metastases’. The proportion of those adverse events attributable to progression of the underlying disease is, for the endpoints ‘Serious adverse events (CTCAE Grade 3–4)’ and ‘Serious SAE’, is so high that the results are subject to uncertainty or cannot be meaningfully interpreted.
  • Regarding the study results:
  • Adverse events (total)
  • With regard to the total number of adverse events in study CA209-017, at least one adverse event was documented for almost every patient, both during treatment with nivolumab and during treatment with docetaxel. This also included events that were not relevant to the patient. The results for the endpoint ‘adverse events’ are used only as supplementary information.
  • Serious adverse events
  • Serious adverse events (SAEs) occurred in 34.4% of patients in the nivolumab group and thus in a smaller proportion of patients than in the docetaxel group, where the figure was 51.2%. Furthermore, the time-adjusted analysis of the median time to the first occurrence of a SAE showed a statistically significant reduction in SAE when nivolumab was compared with docetaxel (hazard ratio: 0.38 [0.25; 0.58], p < 0.001).
  • Severe adverse events (CTCAE Grade 3–4)
  • The results also show an advantage for nivolumab with regard to severe adverse events (CTCAE Grade 3–4) occurring in both treatment groups. Specifically, at least one severe adverse event occurred in 43.5% of patients in the nivolumab group, and thus in significantly fewer patients compared with 72.1% of patients in the docetaxel group. This marked difference is also evident in the time-adjusted analysis of the median time to the first occurrence of a severe adverse event (hazard ratio: 0.25 [0.17; 0.36], p < 0.001).
  • Therapy discontinuation due to adverse events
  • In the nivolumab group, significantly fewer patients discontinued treatment due to adverse events compared with the docetaxel group (10.7% versus 20.2%). The analysis of the median time to therapy discontinuation due to adverse events also showed a statistically significant advantage for nivolumab (hazard ratio: 0.31 [0.16; 0.62], p < 0.001).
  • Specific adverse events
  • In summary, the endpoints relating to side effects consistently show minor harm associated with treatment with nivolumab compared with treatment with docetaxel, and thus an additional benefit for nivolumab due to the reduction in side effects compared with docetaxel.

2) Patients for whom treatment with docetaxel is not indicated

• For patients for whom treatment with docetaxel is not indicated, additional benefit is not proven.
• No relevant data were presented that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.
• There is no study directly comparing nivolumab with best supportive care. The pharmaceutical manufacturer’s argument that the results from study CA209-017 (patients for whom treatment with docetaxel is indicated) are transferable to patients for whom treatment with docetaxel is not indicated is not accepted.

Courtesy translation only, please refer to the German original.