Nivolumab (22) – Opdivo®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer drew on the results of the ongoing, open-label, randomised, parallel-group Phase III registration trial CA209-648 (CheckMate 648), in which either nivolumab in combination with ipilimumab or nivolumab in combination with cisplatin and 5-fluorouracil is compared with cisplatin in combination with 5-fluorouracil.

Adults with advanced, recurrent or metastatic, non-curably treatable squamous cell carcinoma of the oesophagus with tumour cell PD-L1 expression ≥ 1%; first-line treatment

• Consequently, the G-BA has determined that nivolumab in combination with cisplatin and 5-fluorouracil for the first-line treatment of adults with unresectable, advanced, recurrent or metastatic squamous cell carcinoma of the oesophagus with tumour cellPD-L1 expression of ≥ 1 % as having a considerable additional benefit compared with the appropriate comparator therapy, cisplatin in combination with 5-fluorouracil.
• Consequently, the certainty of evidence for the established additional benefit is classified as ‘indication’.
• Mortality – Overall survival
  • In the CheckMate 648 trial, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of nivolumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil.
  • The prolongation of survival time achieved by treatment with nivolumab in combination with cisplatin and 5-fluorouracil is regarded as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • In the Checkmate 648 trial, PFS is defined as the period from randomisation to the first documented occurrence of disease progression or death from any cause, whichever occurs first.
  • A statistically significant difference in PFS was observed between the treatment groups, in favour of the advantage of nivolumab in combination with cisplatin and 5-fluorouracil.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference was found between the treatment arms for the health status endpoint.
• Quality of life – health-related quality of life (assessed using FACT-E)
  • Health-related quality of life was assessed in the CheckMate 648 study using the FACT-E (Functional Assessment of Cancer Therapy-Esophageal) questionnaire.
  • No statistically significant difference was observed between the treatment arms for the health-related quality of life endpoint.
• Side effects
  • Adverse events occurred in almost all participants in the CheckMate 648 study.
  • No statistically significant differences were observed between the treatment arms for the endpoints of adverse events (AEs) and severe adverse events (SAEs) (CTCAE grade ≥ 3).
  • For the endpoint of therapy discontinuations due to AEs (discontinuation of at least one active agent), a statistically significant disadvantage was observed with nivolumab in combination with cisplatin and 5-fluorouracil.
  • For the specific adverse events immune-mediated SAE and immune-mediated severe AE, no statistically significant differences were observed between the treatment groups.
  • Statistically significant advantages in favour of nivolumab in combination with cisplatin and 5-fluorouracil were observed for the specific AEs of vomiting (severe AE) and pneumonia (severe AE).
  • An overall review of the results regarding side effects shows that, for nivolumab in combination with cisplatin and 5-fluorouracil, there is a disadvantage compared with cisplatin in combination with 5-fluorouracil in terms of therapy discontinuations due to adverse events. In detail, there are advantages with regard to specific adverse events.
• Overall assessment
  • Results from the CheckMate 648 trial are available for the benefit assessment of nivolumab in combination with cisplatin and 5-fluorouracil as first-line treatment for adults with unresectable, advanced, recurrent or metastatic squamous cell carcinoma of the oesophagus with tumour cell-PD-L1 expression ≥ 1%, results from the CheckMate 648 trial are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • With regard to overall survival, a statistically significant advantage was observed for nivolumab in combination with cisplatin and 5-fluorouracil. The extent of the prolongation in survival is assessed as a significant improvement.
  • For the endpoints of health status (assessed using the EQ-5D-VAS) and health-related quality of life (assessed using the FACT-E), there are no statistically significant differences between the treatment arms.
  • With regard to side effects, nivolumab in combination with cisplatin and 5-fluorouracil shows a disadvantage compared with cisplatin in combination with 5-fluorouracil in terms of therapy discontinuations due to adverse events. In detail, there are advantages with regard to specific adverse events.
  • Taking the available results on patient-relevant endpoints into account as a whole, the G-BA concludes that the clear advantage in overall survival outweighs the disadvantage in terms of therapy discontinuations due to adverse events. There is a significant improvement in treatment-related benefit that has not been achieved before.

Courtesy translation only, please refer to the German original.