Nivolumab (19) – Opdivo®

• Clinical trials
  • CA209-577 is an ongoing, parallel, double-blind, randomised controlled Phase III trial comparing nivolumab with placebo.

Adults with carcinoma of the oesophagus or the gastro-oesophageal junction and pathological residual disease following prior neoadjuvant chemoradiotherapy; adjuvant treatment

• For the adjuvant treatment of oesophageal or gastro-oesophageal junction carcinomas in adults with pathological residual disease following prior neoadjuvant chemoradiotherapy, an indication of a non-quantifiable additional benefit has been established.
• In the overall assessment, nivolumab is therefore found to offer an indication of a non-quantifiable additional benefit for the adjuvant treatment of oesophageal or gastro-oesophageal junction carcinomas in adults with residual pathological disease following prior neoadjuvant chemoradiotherapy, compared with watchful watchful waiting.
• Overall, an indication is derived regarding the certainty of the findings.
• mortality
  • The pharmaceutical manufacturer has not provided any data on overall survival.
  • The pharmaceutical manufacturer justifies this approach on the grounds that the first interim analysis (data cut-off 3 July 2020) for overall survival was linked to the interim analysis for the primary endpoint of disease-free survival (DFS) and was contingent upon the planned number of DFS events being reached.
  • As neither the planned event numbers nor the specified significance level were met for the first interim analysis or for the data cut-off date required by the EMA (18 February 2021), the overall survival data were not unblinded for the pharmaceutical manufacturer.
  • According to the IQWiG, the failure to unblind the overall survival data is not entirely comprehensible, as the recurrence rate also includes the event ‘death without recurrence’, for which unblinded data are available for each treatment arm.
  • Data on overall survival are considered particularly relevant when assessing the additional benefit of nivolumab in the therapeutic context under consideration here.
• Morbidity – Recurrences (event rate)
  • A statistically significant advantage in favour of nivolumab compared with watchful waiting is evident for the recurrence rate.
  • At the time of the data cut-off, a recurrence had occurred in 50.4% of patients in the nivolumab arm and in 65.3% of patients in the placebo arm.
• Morbidity – Disease-Free Survival (DFS)
  • The time-to-event analysis shows a statistically significant positive effect for nivolumab compared with watchful waiting, which is assessed as a clinical improvement.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • None of the analyses presented showed a statistically significant difference between the treatment arms.
  • The additional benefit of nivolumab for the health status endpoint (EQ-5D-VAS) is not proven.
• Quality of life – FACT-E
  • There is no statistically significant difference between the treatment arms.
  • The additional benefit of nivolumab for the quality of life endpoint category (EQ-5D-VAS) is not proven.
• Side effects – Adverse events (AE)
  • In the CA209-577 study, 96.1% of patients in the intervention arm experienced an adverse event, compared with 92.7% of patients in the control arm.
• Side effects – Serious adverse events (SAEs) and severe AEs (CTCAE grade 3 or 4)
  • No statistically significant differences were observed between nivolumab and watchful waiting for the endpoints of SAE and severe AEs (CTCAE grade ≥ 3).
• Side effects – Discontinuation due to AEs
  • For the endpoint of therapy discontinuation due to an AE, a statistically significant disadvantage was observed relative to nivolumab.
• Side effects – Specific AEs
  • Statistically significant disadvantages were observed for nivolumab with regard to specific AEs.
  • Specifically, there are disadvantages with regard to the endpoints of infections and parasitic diseases (severe UEs) as well as disorders of the blood and lymphatic system (severe UEs).
  • For the endpoints ‘immune-mediated SUEs’ and ‘immune-mediated severe AEs’, no statistically significant difference was observed between the treatment arms in either case.
• Overall assessment
  • Results from the CA209-577 study are available for the assessment of the additional benefit of nivolumab, comparing it with a watch-and-wait approach in terms of morbidity (health status), quality of life and side effects.
  • For the endpoint category of mortality, the pharmaceutical manufacturer did not provide any data from the CA209-577 study.
  • In the morbidity endpoint category, nivolumab shows statistically significant advantages over a watch-and-wait approach in terms of recurrence rate and disease-free survival.
  • Given the fundamentally curative nature of the treatment in question, the prevention of recurrence is relevant to patients.
  • The additional benefit of nivolumab for the health status endpoint (EQ-5D VAS) is not proven.
  • For health-related quality of life, assessed using the FACT-E total score, there is no statistically significant difference between the study arms.
  • With regard to side effects, a disadvantage of nivolumab compared with watchful waiting was observed for the endpoint of discontinuation due to AEs.
  • In detail, disadvantages for nivolumab were also observed with regard to specific AEs.
  • In the category of side effects, therefore, overall disadvantages of nivolumab compared with watchful waiting can be observed.
  • On balance, the positive effect on recurrence is offset by a disadvantage in terms of side effects.
  • The disadvantage in the side effects category does not, on the whole, call into question the positive effect in terms of preventing recurrence.
  • However, due to the lack of data on overall survival and the resulting uncertainties, the additional benefit of nivolumab cannot be quantified.

Courtesy translation only, please refer to the German original.