Nivolumab (23) – Opdivo®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer provided 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 ipilimumab offers considerable added benefit compared with the appropriate comparator therapy—cisplatin in combination with 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 % offers considerable additional benefit compared with the appropriate comparator therapy, cisplatin in combination with 5-fluorouracil.
• Overall, these limitations mean that the certainty of the evidence for the established additional benefit is classified as a ‘hint’.
• mortality
  • Overall survival is defined in the CheckMate 648 trial as the time from randomisation to death from any cause.
  • In the patient population relevant for the analysis, with tumour cell PD-L1 expression ≥ 1 %, 119 patients in the intervention arm (75.3 %) and 130 in the control arm (82.8%). The median survival time was 13.70 months in the intervention arm and 9.07 months in the control arm, corresponding to a median survival benefit of 4.63 months. The time-to-event analysis revealed a statistically significant difference (hazard ratio (HR): 0.63; [95% confidence interval (CI): 0.49; 0.82]; p-value < 0.001).
  • Overall, in the mortality endpoint category, nivolumab in combination with ipilimumab resulted in a prolongation of overall survival compared with cisplatin in combination with 5-fluorouracil, which is considered to have an extensive extent of 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.
  • There is no statistically significant difference in PFS between the treatment groups.
  • 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.
  • There was no statistically significant difference 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 – Total adverse events (AEs)
  • Adverse events occurred in almost all participants in the CheckMate 648 study. The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
• Side effects – serious AEs (SAEs)
  • For the SAE endpoint, a statistically significant difference was observed to the disadvantage of nivolumab in combination with ipilimumab.
• Side effects – Severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs
  • For the endpoints ‘severe AEs (CTCAE grade ≥ 3)’ and ‘therapy discontinuations due to AEs’ (discontinuation of at least one treatment component), no statistically significant differences were observed between the treatment arms.
• Side effects – Specific AEs
  • For specific adverse events, there are both advantages and disadvantages for nivolumab in combination with ipilimumab compared with cisplatin in combination with 5-fluorouracil.
  • Statistically significant advantages were observed in favour of nivolumab in combination with ipilimumab with regard to gastrointestinal disorders (SOC, AE), mucositis (PT, AE), alopecia (PT, AE), hiccups (PT, AE), renal and urinary tract disorders (SOC, AE), vomiting (PT, SAE), anaemia (PT, severe AE, CTCAE grade ≥ 3), low neutrophil count (PT, severe AE, CTCAE grade ≥ 3) and nervous system disorders (SOC, severe AE, CTCAE grade ≥ 3).
  • There are statistically significant disadvantages for nivolumab in combination with ipilimumab with regard to immune-mediated SAE and immune-mediated severe AEs (CTCAE grade ≥ 3).
  • An overall review of the results on side effects shows that nivolumab in combination with ipilimumab is associated with a higher incidence of serious adverse events compared with cisplatin in combination with 5-fluorouracil. In detail, there are both advantages and disadvantages regarding specific adverse events.
• Overall assessment
  • A statistically significant advantage was observed for nivolumab in combination with ipilimumab in terms of overall survival. The extent of the prolongation in survival time is assessed as a marked 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 ipilimumab shows a disadvantage in terms of serious adverse events compared with cisplatin in combination with 5-fluorouracil. In detail, there are both advantages and disadvantages regarding specific adverse events.
  • Taking an overall view of the available results on patient-relevant endpoints, the G-BA concludes that the clear advantage in terms of overall survival outweighs the disadvantage in terms of serious 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.