Pembrolizumab (22) – Keytruda®

• Clinical trials
  • The benefit assessment is based on the results of the randomised, double-blind, placebo-controlled Phase III trial KEYNOTE 564.
  • The trial compares pembrolizumab with placebo.

Adults with renal cell carcinoma who are at increased risk of recurrence following a nephrectomy or following a nephrectomy and resection of metastatic lesions; adjuvant treatment

• mortality
  • overall survival
  • In the KEYNOTE 564 study, overall survival is defined as the time from randomisation to death, regardless of the underlying cause.
  • For the endpoint of overall survival, there is a statistically significant advantage for pembrolizumab compared with watchful waiting.
  • Taking into account the short follow-up period, the minor number of events that occurred, and the remaining uncertainties regarding subsequent treatments, it is concluded that the extent of the improvement in overall survival cannot be reliably quantified.
• Morbidity – Recurrences
  • The endpoint ‘recurrences’ is a composite endpoint comprising local recurrence, distant metastases and death from any cause.
  • Patients in this therapeutic indication are treated with a curative approach as part of adjuvant therapy for renal cell carcinoma following partial nephroprotective or radical nephrectomy (with complete resection of metastatic lesions) and negative surgical margins. 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 therefore clinically relevant to the patient.
  • There is a statistically significant advantage for pembrolizumab over watchful waiting in terms of the recurrence rate and disease-free survival as assessed by the investigators.
  • For the endpoint of relapses, operationalised as disease-free survival, there is also an effect modification by the characteristic of metastasis status (M0 vs. M1 NED), with a clear advantage observed for patients with metastasis status M0 and a very clear advantage for patients with metastasis status M1 NED when pembrolizumab is used compared with watchful waiting.
  • In the additional operationalisations presented in accordance with BICR, a statistically significant advantage was observed for pembrolizumab over watchful waiting in terms of disease-free survival, the event rate and event-free survival.
  • In the overall assessment of the morbidity endpoint category, there is a clear advantage for pembrolizumab over watchful waiting in terms of the recurrence endpoint; however, this finding is subject to uncertainty.
• Health-related quality of life
  • Health-related quality of life was assessed in the KEYNOTE 564 trial using the EORTC QLQ-C30.
  • With regard to health-related quality of life, the analyses based on mean differences showed no statistically significant differences between the treatment groups for the endpoints of global health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning.
• Side effects – severe adverse events (SUEs), severe adverse events (CTCAE grade ≥ 3) and discontinuation due to adverse events
  • For the endpoints SUEs, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs, a statistically significant disadvantage was observed between the treatment groups in favor of pembrolizumab compared with watchful waiting.
  • This disadvantage is classified as moderate for the endpoints SUEs and severe AEs (CTCAE grade ≥ 3) and as marked for discontinuation due to AEs.
  • For severe AEs (CTCAE grade ≥ 3), an effect modification was observed for the characteristic ‘age’. For participants aged < 65 years, a statistically significant effect was observed to cause a disadvantage for pembrolizumab. For participants aged ≥ 65 years, no statistically significant difference was observed.
• Overall assessment
  • The assessment of the additional benefit of pembrolizumab as monotherapy for the adjuvant treatment of adults with renal cell carcinoma who are at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions results on mortality, morbidity, quality of life and side effects are available from the double-blind, randomised, controlled KEYNOTE 564 trial.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of pembrolizumab compared with watchful waiting. However, given the short follow-up periods and the small number of events that occurred, the extent of the improvement cannot be reliably quantified.
  • In the overall assessment of the morbidity results, there is a clear advantage of pembrolizumab in terms of the recurrence endpoint, although this is subject to uncertainty. The prevention of recurrence represents an essential therapeutic goal in the present curative treatment setting.
  • For the patient-reported endpoints in the categories of morbidity (assessed using the FKSI-DRS, EORTC QLQ-C30 and EQ-5D VAS) and health-related quality of life (assessed using the EORTC QLQ-C30), there are no advantages or disadvantages for pembrolizumab compared with watchful waiting.
  • In the side effect category, there are moderate differences in the endpoints of SAE and severe AE (CTCAE grade ≥ 3), as well as significant differences in therapy discontinuations due to AE between the treatment arms, with a disadvantage for pembrolizumab compared with watchful waiting. In detail, disadvantages are evident, amongst other things, in immune-mediated SUEs and immune-mediated AEs.
  • Overall, the advantages – improved overall survival and prevention of recurrence – are offset by significant disadvantages in terms of side effects, which also led to a marked increase in therapy discontinuations due to AEs in the study.
  • In its cost-benefit analysis, the G-BA concludes that the advantages of treatment with pembrolizumab – in particular the significant advantage in preventing recurrence – clearly outweigh the disadvantages associated with side effects. However, even taking into account the limitations in assessing the extent of the improvement in overall survival and in recurrence rates, the conclusion that there is a considerable additional benefit does not appear to be justified on the basis of the available data.

Courtesy translation only, please refer to the German original.