Nivolumab (14) – Opdivo®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the open-label, randomised, controlled ATTRACTION-3 trial comparing nivolumab with monochemotherapy using docetaxel or paclitaxel.

a) Adult patients with unresectable, advanced, recurrent or metastatic oesophageal cancer with squamous cell histology, following prior fluoropyrimidine- and platinum-based combination chemotherapy, for whom chemotherapy is a suitable treatment option

• Hint of a minor additional benefit.
• Consequently, the G-BA concludes that there is evidence of a minor additional benefit for nivolumab compared with the appropriate comparator therapy.
• mortality
  • In the ATTRACTION-3 trial, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, there is a statistically significant difference between the treatment groups in favour of nivolumab; given the remaining life expectancy of patients in the present treatment situation, the extent of this difference is considered a relevant improvement.
  • For the endpoint of overall survival, there is a statistically significant advantage of nivolumab compared with docetaxel or paclitaxel; given the remaining life expectancy of patients in this treatment setting, the extent of this advantage is considered a relevant improvement.
• Morbidity – Progression-free survival
  • In the ATTRACTION-3 study, radiological progression-free survival (PFS) was defined as the time from randomisation to radiologically confirmed progression or to death, regardless of the underlying cause of death.
  • No statistically significant difference in PFS was observed between the treatment groups.
  • Morbidity was assessed not primarily on the basis of disease symptoms, but solely on the basis of asymptomatic findings not directly relevant to the patient.
  • Overall, therefore, no advantage or disadvantage can be identified in the morbidity endpoint category. No data on disease symptoms are available.
• Morbidity – Health status (EQ-5D VAS)
  • In the ATTRACTION-3 study, health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
• quality of life
  • Health-related quality of life was not assessed in the ATTRACTION-3 study.
  • Data on health-related quality of life are considered particularly important, especially at this advanced stage of the disease and treatment, where the aim of therapy is palliative.
• Side effects – Adverse events
  • The results for the endpoint ‘Total adverse events’ are presented solely for supplementary purposes. No significant difference was observed between the treatment groups.
• Side effects – serious AEs
  • For the endpoint ‘serious adverse events’, no statistically significant difference was observed between the treatment groups.
• Side effects – severe AEs (CTCAE grade ≥ 3)
  • With regard to the time to onset of severe adverse events with a CTCAE grade of ≥ 3, a statistically significant advantage was observed between the treatment groups in favour of nivolumab.
• Side effects – Discontinuation due to AEs
  • For the endpoint of discontinuation due to AEs, there was no statistically significant difference between the treatment groups.
• Side effects – Specific AEs
  • In detail, the following specific adverse events were observed: stomatitis (AEs), general disorders and administration site conditions (AEs), decreased appetite (AEs), alopecia (AEs), musculoskeletal, connective tissue and bone disorders (AEs), nervous system disorders (AEs), febrile neutropenia (SUEs), hyponatraemia (severe AEs), investigations (severe AEs) and disorders of the blood and lymphatic system (severe AEs), each showing a statistically significant advantage for nivolumab.
• Overall assessment
  • When the endpoints relating to side effects are considered as a whole, a relevant overall advantage is observed for treatment with nivolumab.
  • An overall review of the available results shows an improvement in overall survival and in side effects. No data on health-related quality of life are available; furthermore, no conclusions can be drawn regarding the impact on disease symptoms. The extent of the improvement in therapeutic benefit is assessed overall as a relevant improvement, but no more than a minor one. Consequently, a minor additional benefit is identified for nivolumab compared with treatment with docetaxel or paclitaxel.
• Certainty of the findings (probability of additional benefit)
  • The potential for bias is assessed as low for the endpoint of overall survival.
  • The potential for bias regarding the results for the endpoints ‘serious, non-serious specific adverse events’ and ‘discontinuation due to adverse events’ is assessed as high.
  • Furthermore, there is uncertainty in the overall conclusion regarding additional benefit in that no conclusions can be drawn regarding health-related quality of life and disease symptoms, as these are considered of great importance at the advanced stage of disease and treatment presented here, where the aim of therapy is palliative.
  • Taken together, these limitations mean that the certainty of the findings regarding the identified additional benefit is classified as a ‘hint’.

b) Adult patients with unresectable, advanced, recurrent or metastatic oesophageal cancer with squamous cell histology, following prior fluoropyrimidine- and platinum-based combination chemotherapy, for whom chemotherapy is not a suitable treatment option

• An additional benefit is not proven.
• No data are available from the ATTRACTION-3 study on the basis of which the patient population can be assessed. Consequently, additional benefit is not proven for nivolumab.

Courtesy translation only, please refer to the German original.