Nivolumab (33) – Opdivo®

b) Adults with muscle-invasive urothelial carcinoma with tumour cell PD-L1 expression ≥ 1 per cent and a high risk of recurrence following complete resection, who are unsuitable for cisplatin--based therapy or have already received neoadjuvant chemotherapy with cisplatin; adjuvant treatment

• mortality
  • overall survival
  • In the CA209-274 study, overall survival is defined as the time between randomisation and death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed between the treatment groups in favour of nivolumab.
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
• Morbidity – Failure of the curative treatment approach (event rate and disease-free survival (DFS))
  • In this therapeutic indication, curative therapy is in principle possible and is the aim of treatment.
  • The occurrence of a recurrence following an R0 resection means that the curative treatment approach has failed in this line of treatment.
  • In the CA209-274 study, the failure of the curative treatment approach was not directly assessed as an endpoint.
  • For the purposes of this assessment, the events recorded as part of the composite endpoint DFS in the CA209-274 study are considered, by way of approximation, to operationalise the endpoint.
  • According to the information in the Statistical Analysis Plan, the DFS endpoint was defined as the time from randomisation to the first occurrence of any of the following events: local recurrence within the urinary tract, local recurrence outside the urinary tract, distant recurrence, death from any cause (without prior recurrence).
  • The event rates show a statistically significant difference in favour of nivolumab, demonstrating a clear advantage in preventing the failure of curative treatment compared with a watch-and-wait approach.
  • Furthermore, the event-time analysis – which also takes into account the time to event onset – reveals a significant advantage for nivolumab in terms of disease-free survival (DFS).
  • Subgroup analyses of the event rate indicate an effect modification for the characteristic ‘gender’.
  • A statistically significant advantage in favour of nivolumab was observed in male patients.
  • In female patients, however, no statistically significant difference was observed between the treatment groups.
  • In contrast, the subgroup analyses for DFS show no effect modification for the characteristic ‘gender’.
• Health-related quality of life
  • Health-related quality of life was assessed in the CA209-274 study using the EORTC QLQ-C30 questionnaire.
  • Responder analyses were presented for the time to the first deterioration of ≥ 10 points, which are used for the present benefit assessment.
  • For health-related quality of life assessed using the EORTC QLQ-C30, no statistically significant differences were observed between the treatment arms for the endpoints ‘global health status’, ‘physical functioning’, ‘role functioning’, ‘cognitive functioning’, ‘emotional functioning’ and ‘social functioning’ respectively.
  • Overall, therefore, no advantage or disadvantage was identified for the health-related quality of life endpoint category.
• Side effects – Total adverse events (AEs)
  • In the CA209-274 study, an AE occurred in almost all patients in both the control and intervention arms.
  • The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of nivolumab as monotherapy for the adjuvant treatment of muscle-invasive urothelial carcinoma (MIUC) with tumour cellPD-L1 expression ≥ 1% in adults at high risk of recurrence following radical resection of MIUC, who are unsuitable for cisplatin-containing therapy or have already received neoadjuvant chemotherapy with cisplatin, are presented here: data on mortality, morbidity, health-related quality of life and side effects from the ongoing, double-blind, randomised, controlled Phase III trial CA209-274.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of nivolumab compared with watchful waiting.
  • The extent of the prolongation in overall survival achieved is regarded as a significant improvement.
  • Data on subsequent treatments in the CA209-274 study indicate that no patient any patient received treatment with enfortumab vedotin in combination with pembrolizumab, which represents a highly effective treatment option and the current standard of care for patients in first-line therapy for unresectable or metastatic urothelial carcinoma.
  • In the morbidity endpoint category, the failure of the curative treatment approach – expressed as the event rate and disease-free survival (DFS) – as well as disease-related symptoms (EORTC QLQ-C30) and health status (EQ-5D VAS).
  • In summary, within the morbidity endpoint category, there is a clear advantage of nivolumab in terms of preventing the failure of the curative treatment approach, which is associated with a significant difference in disease-free survival (DFS) in favour of nivolumab.
  • Furthermore, an advantage is evident in terms of health status.
  • No significant difference was observed between the treatment arms in the endpoints relating to symptoms.
  • With regard to health-related quality of life, as assessed using the EORTC QLQ-C30, neither an advantage nor a disadvantage of nivolumab compared with watchful waiting was observed.
  • In the overall analysis of the results on side effects, no statistically significant differences were observed between the treatment arms for SAE and severe AEs.
  • With regard to therapy discontinuations due to AEs, nivolumab was found to have a disadvantage.
  • In detail, advantages and disadvantages were observed for individual specific adverse events.
  • Overall, due to the increase in therapy discontinuations due to AEs, a disadvantage of nivolumab compared with watchful waiting can be identified.
  • On balance, the clear advantages in overall survival, in preventing failure of the curative approach, and in improving health status are offset only by a disadvantage resulting from the increase in therapy discontinuations due to AEs.

Courtesy translation only, please refer to the German original.