Nivolumab (11) – Opdivo®

Adult patients following complete resection of melanoma with lymph node involvement or metastasis, for adjuvant treatment

• mortality
  • overall survival
  • In the CA209-238 study, the analysis of overall survival was not planned a priori for any of the available data sets, nor did the pharmaceutical manufacturer carry out an analysis of any of the endpoints.
  • For the CA184-029 study, the pharmaceutical manufacturer did not provide any data for the patient population with stage IIIB/C disease.
  • Consequently, no data are available for the indirect comparison of the endpoint ‘overall survival’.
• 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. Nevertheless, tumour cells may remain and cause a recurrence at a later stage. A recurrence means that the attempt at a cure through the curative therapeutic approach was unsuccessful. The occurrence of a recurrence is clinically relevant to the patient.
  • For the endpoint of recurrence, a statistically significant advantage of nivolumab over placebo was observed in the patient population with stage IIIB/C disease (relative risk: 0.60 [0.48; 0.73]; p-value: < 0.001). This is based on 133 events (36.1%) in the nivolumab arm of the CA209-238 study (ipilimumab: 177 events, 48.4 per cent) and 258 events (66.5 per cent) in the placebo arm of the CA184-029 trial (ipilimumab: 200 events, 53.1 per cent).
  • 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 (HR: 0.49 [0.37; 0.66]; p-value: < 0.001). In the nivolumab arm of the CA209-238 trial, the median time to event was not reached (ipilimumab: 25.53 months). In the placebo arm of the CA184-029 study, this was 11.30 months (ipilimumab: 18.89 months).
  • The analyses of the endpoints of recurrence and RFS in the CA209-238 study are based on the interim analysis of 14 December 2017, with a minimum follow-up period of 24 months. The probability of recurrence is highest in the first three years. However, the median follow-up duration for patients in the nivolumab arm of the CA209-238 study was only 25 months as at 14 December 2017. Consequently, there are uncertainties regarding the endpoints of recurrence and RFS due to the short follow-up duration.
  • Overall, in the adjusted indirect comparison for patients with stage IIIB/C disease, the endpoints of recurrence and RFS show a very clear, clinically relevant advantage of nivolumab compared with the appropriate comparator therapy, watchful waiting.
• Health-related quality of life
  • Health-related quality of life was assessed in the CA209-238 and CA184-029 studies using the functional scales and the global health status scale of the EORTC QLQ-C30. The time to the first deterioration in the respective score by at least 10 units was analysed.
  • 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, the results on health-related quality of life are considered unusable, in line with the explanations provided in the ‘Symptoms’ section.
• Side effects – Serious adverse events (SAEs), severe AEs (CTCAE Grade 3–4)
  • Due to the high proportion of potentially informative censored data in the nivolumab arm of study CA209-238 and in the placebo arm of study CA184-029, the results regarding SAE and severe AEs (CTCAE Grade 3–4) are considered unusable in the context of an indirect comparison.
• Overall assessment
  • 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). Nivolumab was compared with placebo (watchful waiting) via the bridge comparator ipilimumab.
  • As the disease stages covered by studies CA209-238 (stage IIIB/C, IV) and CA184-029 (stage IIIA–C) are not entirely identical, the adjusted indirect comparison for the overlapping patient populations at stage IIIB/IIIC was used for the present assessment.
  • No usable data are available for the overall survival endpoint.
  • In the morbidity endpoint category, nivolumab demonstrates statistically significant, very clear advantages over watchful waiting in terms of recurrence rate and recurrence-free survival. The prevention of recurrence represents an essential therapeutic goal in the present curative treatment setting. However, there are significant uncertainties regarding the endpoints of recurrence and recurrence-free survival due to the short duration of follow-up.
  • 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 differences in data collection strategies between the CA209-238 and CA184-029 studies.
  • With regard to side effects, nivolumab shows a disadvantage compared with a watch-and-wait approach due to therapy discontinuations caused by adverse events; the extent of this disadvantage is assessed as minor. Significant uncertainties arise in the overall assessment of side effects, as it is not possible to draw conclusions regarding serious adverse events (SAEs), severe adverse events (CTCAE Grade 3–4) and immune-mediated adverse events, particularly due to the high proportion of potentially informative censored data.
  • In light of the available results from the indirect comparison for the patient population with disease stage IIIB/C and the statements from medical societies, it is considered plausible in this specific assessment situation to to extrapolate the results to the other patients in disease stages IIIA and IV covered by the indicated therapeutic indication.

Courtesy translation only, please refer to the German original.