Nivolumab (15) – Opdivo®

• Clinical trials
  • The IMMUNED trial is a three-arm, multicentre, double-blind RCT comparing nivolumab with nivolumab in combination with ipilimumab, and with placebo.

Adjuvant treatment of melanoma with lymph node involvement or metastasis following complete resection in adults

• mortality
  • For patients with stage IIIB/C disease, data are available from the adjusted indirect comparison of the CA209-238 and CA184-029 trials.
  • Due to the aforementioned differences in the standard of care regarding the available follow-up therapies following recurrence between the two studies, the results for the endpoint of overall survival from the two studies are not comparable in substance and cannot be used for an indirect comparison.
  • The pharmaceutical manufacturer has submitted sensitivity analyses in this regard as proof of the robustness of the observed effect.
  • Overall, the sensitivity analyses are not considered sufficient to be used for the indirect comparison.
• Morbidity – Recurrences / Recurrence-free survival (RFS)
  • Patients in the present therapeutic indication are treated with a curative therapeutic approach as part of adjuvant treatment for melanoma following complete resection.
  • The occurrence of a recurrence is clinically relevant.
  • For the endpoint of recurrence, a statistically significant advantage of nivolumab over placebo is observed in the patient population with stage IIIB/C disease.
  • Compared with placebo, nivolumab results in a statistically significant prolongation of the time to recurrence or death in the patient population with stage IIIB/C disease.
  • Overall, therefore, with regard to the endpoints of recurrence and RFS, a clear, clinically relevant advantage of nivolumab over the appropriate comparator therapy—watchful waiting—is observed in the adjusted indirect comparison for patients with stage IIIB/C disease.
• Morbidity – Symptoms
  • Symptoms were assessed in the CA209-238 and CA184-029 studies using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • Due to the different data collection strategies used in studies CA209-238 and CA184-029, the data on disease symptoms are generally considered unusable for an indirect comparison.
• Morbidity – Health status
  • The health status endpoint, assessed using the EQ-5D VAS, was recorded exclusively in study CA209-238; consequently, no adjusted, indirect comparison can be carried out on the basis of this endpoint.
• quality of life
  • Health-related quality of life was assessed in studies CA209-238 and CA184-029 using the functional scales and the global health status scale of the EORTC QLQ-C30.
  • The limitations of the data mentioned in connection with the assessment of disease symptoms, due to differing measurement strategies in studies CA209-238 and CA184-029, apply equally to the assessment of health-related quality of life.
  • Consequently, in line with the explanations provided in the ‘Symptoms’ section, the results on health-related quality of life are considered unusable.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all study participants.
• Side effects – Serious adverse events (SAEs), severe AEs (CTCAE Grade 3–4)
  • For the endpoints SAE and severe AEs (CTCAE grade ≥ 3), the adjusted indirect comparison showed no statistically significant differences between nivolumab and placebo.
• Side effects – Therapy discontinuation due to AEs
  • In the adjusted indirect comparison, there was a statistically significant disadvantage for nivolumab compared with placebo regarding the endpoint of discontinuation due to adverse events.
• Side effects – Immune-mediated AEs
  • The data on immune-mediated AEs are considered unusable due to insufficient information on the operationalisation of immune-mediated AEs.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of nivolumab as monotherapy for the adjuvant treatment of melanoma with lymph node involvement or metastasis following complete resection, results are available on morbidity, quality of life and side effects compared with the appropriate comparator therapy (watchful waiting).
  • This assessment is based on an adjusted indirect comparison of the studies CA209-238 (nivolumab vs. ipilimumab) and CA184-029 (placebo vs. ipilimumab) according to Bucher.
  • No usable data are available for the endpoint of overall survival.
  • In the morbidity endpoint category, nivolumab shows statistically significant, clear advantages over a watch-and-wait approach for the IIIB/C patient population in terms of recurrence rate and recurrence-free survival.
  • The prevention of recurrence represents an essential therapeutic goal in the present curative treatment setting.
  • The data submitted by the pharmaceutical manufacturer on patient-reported endpoints in the categories of morbidity and health-related quality of life are considered unusable due to differing data collection strategies in the CA209-238 and CA184-029 (EORTC QLQ-C30) and the exclusive use of the EQ-5D VAS in study CA209-238, respectively, are not considered usable.
  • With regard to side effects, there are no relevant differences between the treatment arms in terms of the endpoints severe adverse events (SAE) and severe adverse events (CTCAE grade 3–4).
  • By contrast, nivolumab shows a disadvantage compared with watchful waiting in terms of therapy discontinuations due to adverse events.
  • In light of the available results from the indirect comparison for the patient population with stage IIIB/C disease and the statements from medical societies, it is considered plausible in this specific assessment context to to extrapolate the results to patients with stage IIIA and IV disease.
  • When the available results are considered as a whole, nivolumab offers an advantage over a ‘watch-and-wait’ approach for the endpoints of recurrence and recurrence-free survival alone.
  • The positive effect is clear and is based on robust data from a sufficiently long follow-up period.
  • In the present adjuvant treatment context, the prevention of recurrence is an essential treatment objective.
  • The disadvantage in terms of side effects is weighed against the aim of curative treatment and does not lead to a downgrading of the additional benefit.
  • Overall, there is a hint of considerable additional benefit for nivolumab compared with watchful waiting.

Courtesy translation only, please refer to the German original.