Pembrolizumab (37) – Keytruda®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has included in the dossier the results of the ongoing, double-blind, randomised, controlled KEYNOTE 522 trial, in which pembrolizumab in combination with chemotherapy for neoadjuvant treatment and subsequently as monotherapy for adjuvant treatment following surgery is compared with placebo in combination with chemotherapy for neoadjuvant treatment and subsequently with placebo for adjuvant treatment following surgery.

a) Pembrolizumab in combination with paclitaxel and carboplatin, followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant)

• For pembrolizumab in combination with paclitaxel and carboplatin, followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab monotherapy (adjuvant) for the treatment of adults with locally advanced or early-stage triple-negative breast cancer with a high risk of recurrence, there is an indication for a minor additional benefit.
• The certainty of the evidence for the identified additional benefit is classified as ‘indication’.
• mortality
  • Overall survival was defined in the KEYNOTE 522 trial as the period from randomisation to death, regardless of the underlying cause.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of the combination therapy with pembrolizumab. The extent of the prolongation in overall survival achieved is assessed as a relevant improvement.
• Morbidity – Failure of curative treatment (event rate and event-free survival)
  • Patients in this therapeutic indication are treated with a curative therapeutic approach. The failure of a curative therapeutic approach is, in principle, relevant to patients.
  • In this benefit assessment, the endpoint is considered in terms of both the event rate and event-free survival. Both analyses include the following events: local progression preventing definitive surgery; local progression preventing surgery; positive resection margin at the last operation; local recurrence; distant recurrence; distant metastases; second primary tumour; death from any cause.
  • Both the event rate and event-free survival show a statistically significant advantage for pembrolizumab in combination with (neoadjuvant) chemotherapy followed by (adjuvant) pembrolizumab compared with the appropriate comparator therapy.
  • When considering both endpoints, a considerable overall advantage was observed for pembrolizumab in combination with paclitaxel and carboplatin, followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant).
• quality of life
  • The pharmaceutical manufacturer provides analyses in the dossier for the 7th data cut-off for the EORTC QLQ-C30 and EORTC QLQ-BR23 scales.
  • As previously described for the ‘symptoms’ endpoint, no evaluable data are available for the ‘quality of life’ endpoint.
• Side effects – Serious adverse events (SAEs) and discontinuation due to AEs
  • For the endpoints SAE and discontinuation due to AEs, there is a statistically significant disadvantage for the combination therapy with pembrolizumab compared with the appropriate comparator therapy in each case.
• Overall assessment
  • In the mortality endpoint category, a statistically significant advantage in favour of the combination therapy with pembrolizumab is observed for the overall survival endpoint. The extent of the prolongation achieved in overall survival is assessed as a relevant improvement.
  • In the morbidity category, with regard to the failure of the curative treatment approach – operationalised via the event rate and event-free survival – a statistically significant advantage in favour of pembrolizumab in combination with paclitaxel and carboplatin, followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant).
  • No evaluable data are available for the endpoints of symptoms and health status.
  • Similarly, no evaluable data are available for the quality of life endpoint category.
  • With regard to side effects, statistically significant disadvantages were observed for the endpoints of serious adverse events (SAE) and discontinuation due to AEs for treatment with pembrolizumab in combination with paclitaxel and carboplatin followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant), and in detail for the specific AEs.
  • On balance, the relevant improvement in overall survival and the relevant advantage in terms of preventing failure of the curative treatment approach are offset by disadvantages relating to side effects. The disadvantages relating to side effects are weighed against the fact that preventing recurrence is an essential therapeutic objective in the present curative treatment context.
  • In its balanced assessment, the G-BA concludes that the advantages in terms of overall survival and the prevention of failure of the curative treatment approach outweigh the disadvantages associated with side effects, and that, overall, there is a significant improvement in treatment-related benefit.
  • For pembrolizumab in combination with paclitaxel and carboplatin, followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant), compared with treatment with paclitaxel and carboplatin followed by doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and watchful waiting (adjuvant) in the treatment of locally advanced or early-stage triple-negative breast cancer with a high risk of recurrence, which results in a minor additional benefit.

b) Pembrolizumab in combination with a chemotherapy regimen other than paclitaxel and carboplatin, followed by pembrolizumab in combination with a chemotherapy regimen other than doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant)

• For pembrolizumab in combination with a chemotherapy other than paclitaxel and carboplatin, followed by pembrolizumab in combination with a chemotherapy other than doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant) for the treatment of adults with locally advanced or early-stage triple-negative breast cancer with a high risk of recurrence, an additional benefit is not proven.

Courtesy translation only, please refer to the German original.