Nivolumab (21) – Opdivo®

• Clinical trials
  • The CheckMate 274 trial is a multicentre, parallel-group, double-blind, randomised, controlled Phase III trial, which has been ongoing since March 2016, comparing nivolumab with placebo.

a) Adults with muscle-invasive urothelial carcinoma with tumour cell PD-L1 expression ≥ 1% and a high risk of recurrence following complete resection, who are suitable for cisplatin-containing therapy; adjuvant treatment

• An additional benefit is not proven.
• For the adjuvant treatment of muscle-invasive urothelial carcinoma with tumour cell PD-L1 expression ≥ 1 % in adults at high risk of recurrence following radical resection who are suitable for cisplatin-based therapy, the pharmaceutical manufacturer has not submitted any data for the assessment of additional benefit.

b) Adults with muscle-invasive urothelial carcinoma with tumour cell PD-L1 expression ≥ 1% and a high risk of recurrence following complete resection, who are not suitable for cisplatin-containing therapy or who have already received neoadjuvant treatment; adjuvant treatment

• Hint for a non-quantifiable additional benefit
• On balance, the positive effects on recurrence and health status are offset by a disadvantage in terms of side effects.
• However, given the lack of data on overall survival, the extent of the additional benefit cannot be quantified in the overall assessment.
• mortality
  • The pharmaceutical manufacturer has not provided any data on overall survival.
  • The pharmaceutical manufacturer justifies its approach on the grounds that the first interim analysis (2nd data cut-off: February 2021) for overall survival was linked to the interim analysis for the primary endpoint of disease-free survival (DFS) and was contingent upon reaching the planned number of DFS events.
  • According to the IQWiG, the failure to unblind the data on overall survival is not entirely comprehensible, as – at least for the first data cut-off (August 2020) – information on the number of patients who had died, unblinded by treatment arm, is available from the side effect analyses in the study report.
• Morbidity – Recurrences (event rate)
  • For the recurrence rate, there is a statistically significant advantage in favour of nivolumab compared with watchful waiting.
  • The recurrence rate endpoint comprises the same individual components and thus the same recurrence events, as well as deaths prior to recurrence as an additional component, as does the DFS endpoint.
• Morbidity – Disease-Free Survival (DFS)
  • The time-to-event analysis shows a statistically significant benefit in favour of nivolumab compared with watchful waiting.
  • An overall review of the results on recurrence reveals a statistically significant advantage of nivolumab compared with watchful waiting, the extent of which is assessed as a clinical improvement.
• Morbidity – Symptoms (assessed using the EORTC QLQ-C30)
  • There are therefore no statistically significant differences between the treatment arms for the symptom-related endpoints.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • With regard to the health status endpoint (EQ-5D VAS), a statistically significant difference in favour of nivolumab is observed.
• Health-related quality of life (assessed using the EORTC QLQ-C30)
  • There is therefore no statistically significant difference between the treatment arms for any of the endpoints: overall health status, cognitive functioning, social functioning, physical functioning, role functioning and emotional functioning.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all participants in the CheckMate 274 trial.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3)
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE and severe AEs (CTCAE grade ≥ 3).
• Side effects – Therapy discontinuations due to AEs
  • For the endpoint of therapy discontinuations due to AEs, there was a statistically significant difference to the detriment of nivolumab compared with placebo.
• Side effects – Specific AEs
  • For the endpoints immune-mediated SAE, immune-mediated severe AEs, disorders of the skin and subcutaneous tissue (AE), asthenia (AE), disorders of the respiratory tract, thoracic cavity and mediastinum (SAE), and elevated lipase (severe AE), a statistically significant disadvantage was observed in each case compared with placebo.
  • Statistically significant advantages in favour of nivolumab were observed for the specific AEs ‘infections and parasitic diseases’ (severe SAE) and ‘gastrointestinal disorders’ (severe SAE).
  • An overall review of the results on side effects shows that nivolumab has a disadvantage in terms of higher rates of therapy discontinuation due to AEs compared with placebo.
• Overall assessment
  • For the assessment of the additional benefit of nivolumab, results from the CheckMate 274 trial are available comparing it with a watch-and-wait approach in terms of morbidity, quality of life and side effects.
  • No data were submitted by the pharmaceutical manufacturer for the endpoint category of mortality. However, data on overall survival are considered particularly relevant when assessing the additional benefit of nivolumab in the present treatment context.
  • In the morbidity endpoint category, nivolumab demonstrates a relevant advantage over a watch-and-wait approach in terms of preventing relapses. Given the fundamentally curative nature of the treatment in question, preventing relapses is a significant therapeutic objective.
  • With regard to symptoms, there is no statistically significant difference between the treatment arms.
  • With regard to the health status endpoint (EQ-5D VAS), there is a statistically significant difference in favour of nivolumab.
  • For the endpoint category of health-related quality of life, there is no statistically significant difference between the treatment arms.
  • With regard to side effects, a disadvantage of nivolumab compared with watchful waiting was observed for the endpoint ‘therapy discontinuation due to AEs’. In detail, there are also advantages and disadvantages for nivolumab with regard to specific AEs. In the ‘side effects’ category, therefore, an overall disadvantage of nivolumab compared with watchful waiting can be observed.
  • In the overall assessment, the positive effects on recurrence and health status are offset by a disadvantage in terms of side effects.
  • However, given that no data on overall survival are available, the extent of the additional benefit cannot be quantified in the overall assessment.

Courtesy translation only, please refer to the German original.