Nivolumab (32) – Opdivo®

• Clinical trials
  • The CA209-577 trial is a parallel, double-blind, randomised, controlled Phase III trial in which nivolumab was compared with placebo.

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

• Hint for a minor additional benefit
• In the overall assessment, nivolumab is therefore found to offer a minor additional benefit over a watch-and-wait approach for the adjuvant treatment of oesophageal or gastro-oesophageal junction carcinomas in adults with pathological residual disease following prior neoadjuvant chemoradiotherapy.
• Due to uncertainties arising from effect modifications, a hint regarding the certainty of the findings is derived overall.
• mortality
  • In the CA209-577 trial, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment arms for the endpoint of overall survival.
  • The subgroup analysis reveals effect modifications due to the characteristics ‘site of the disease’ and ‘pathological tumour status’. In the patient population of patients with oesophageal carcinoma, a statistically significant advantage was observed in favour of nivolumab, whilst no statistically significant difference was observed for patients with gastro-oesophageal junction carcinoma.
  • In the patient population of patients with a pathological tumour status of ypT0 and ypT1/ypT2, there is a statistically significant advantage for nivolumab, whilst no statistically significant difference is observed in the patient population with a pathological tumour status of ypT3/ypT4.
  • These results are not considered to provide a sufficient basis for an overall assessment of the additional benefit for clearly definable patient populations.
• Morbidity – Recurrences (recurrence rate and disease-free survival (DFS))
  • Patients in the present therapeutic indication are treated with a curative therapeutic approach. The failure of a curative therapeutic approach is, in principle, relevant to patients.
  • With regard to the endpoints of recurrence rate and disease-free survival, there is a statistically significant advantage of nivolumab compared with watchful waiting.
  • In the present curative treatment setting, the prevention of recurrence is an essential treatment objective.
• Morbidity – Health status
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • There is no statistically significant difference between the treatment arms.
  • The subgroup analysis revealed an effect modification by the characteristic ‘gender’. For female participants, there was a statistically significant advantage in favour of nivolumab, whilst for male participants there was a statistically significant disadvantage for nivolumab.
  • These subgroup results are not considered sufficient to draw separate conclusions regarding additional benefit in the overall assessment.
• Quality of life – FACT-E
  • Health-related quality of life was assessed in the CA209-577 study using the FACT-E questionnaire.
  • There is no statistically significant difference for the FACT-E endpoint.
• Side effects – Total adverse events (AEs)
  • In the CA209-577 study, 96.8% of patients in the intervention arm experienced an adverse event, compared with 92.7% of patients in the control arm. The results are presented for supplementary information only.
• Side effects – Serious adverse events (SAEs) and severe AEs (CTCAE Grade 3 or 4)
  • No statistically significant differences were observed between the treatment groups for the endpoints SAE and severe AEs (CTCAE grade ≥ 3).
• Side effects – Therapy discontinuation due to AEs
  • For the endpoint of therapy discontinuation due to an AE, a statistically significant difference was observed to the detriment of nivolumab.
• Side effects – Specific AEs
  • In detail, nivolumab showed disadvantages for the following endpoints relating to specific AEs: immune-mediated AEs, disorders of the skin and subcutaneous tissue, infections and parasitic diseases, and disorders of the blood and lymphatic system.
  • For the endpoint ‘immune-mediated severe adverse events’, there was no statistically significant difference between the treatment arms.
  • In the overall assessment of the results regarding side effects, a disadvantage for nivolumab is identified due to the higher rate of therapy discontinuations and, in detail, the specific AEs.
• Overall assessment
  • For the re-evaluation following the expiry of the authorisation for nivolumab as adjuvant treatment for oesophageal cancer or cancer of the gastro-oesophageal junction in adults with pathological residual disease following prior neoadjuvant chemoradiotherapy, results from the CA209-577 trial are available comparing nivolumab with a watch-and-wait approach in terms of mortality, morbidity, quality of life and side effects.
  • With regard to the endpoint of overall survival, there is no statistically significant difference between the treatment arms.
  • For the endpoints of recurrence rate and disease-free survival, nivolumab showed a statistically significant advantage over watchful waiting. In the present curative treatment setting, the prevention of recurrence is an essential treatment goal.
  • With regard to health status (EQ-5D VAS), there is no statistically significant difference between the treatment arms.
  • There is no statistically significant difference for the FACT-E total score endpoint.
  • Overall, the positive effect on recurrence is offset by a disadvantage in terms of side effects. Although the positive effect in terms of preventing relapses is not supported by further advantages in other patient-relevant endpoints, the disadvantage does not call into question the positive effect in terms of preventing relapses. The extent of the improvement in therapeutic benefit is assessed overall as a relevant improvement, but no more than a minor one.
  • In the overall assessment, nivolumab is therefore found to offer a minor additional benefit compared with a ‘watch-and-wait’ approach for the adjuvant treatment of oesophageal or gastro-oesophageal junction carcinomas in adults with residual pathological disease following prior neoadjuvant chemoradiotherapy.

Courtesy translation only, please refer to the German original.