Pembrolizumab (21) – 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)

• The certainty of the evidence is classified overall as a hint.
• Overall, therefore, there is a hint of a minor additional benefit of pembrolizumab + paclitaxel + carboplatin followed by pembrolizumab + doxorubicin/epirubicin + cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant).
• mortality
  • Overall survival was defined in the KEYNOTE 522 trial as the period from randomisation to death, regardless of the underlying cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• Morbidity – Recurrences (recurrence rate and event-free survival)
  • In this benefit assessment, recurrences are examined using both the recurrence rate and event-free survival as endpoints.
  • A statistically significant advantage in favour of pembrolizumab in combination with chemotherapy (neoadjuvant followed by pembrolizumab (adjuvant)) compared with the appropriate comparator therapy is evident for both the recurrence rate and event-free survival.
  • When both endpoints are considered, a considerable overall advantage in terms of preventing recurrence is observed for pembrolizumab in combination with paclitaxel and carboplatin, followed by pembrolizumab in combination with doxorubicin or epirubicin and cyclophosphamide (neoadjuvant) and pembrolizumab (adjuvant).
• Morbidity – Pathological complete response (pCR)
  • The endpoint ‘pathological complete response’ (ypT0/Tis ypN0) is one of the two co-primary endpoints in the KEYNOTE 522 trial and was defined in the trial as the proportion of patients in whom no invasive tumour cells were detected in the resected specimen from the breast and regional lymph nodes.
  • For the pathological complete remission endpoint, there is a statistically significant difference in favour of pembrolizumab in combination with (neoadjuvant) chemotherapy, followed by pembrolizumab (adjuvant), compared with the appropriate comparator therapy.
  • Overall, pCR does not currently represent a valid surrogate endpoint for patient-relevant endpoints.
• Morbidity – Breast-conserving surgery (BCS)
  • The endpoint ‘breast-conserving surgery (BCS)’ is defined in the KEYNOTE 522 trial as the proportion of patients who were able to undergo breast-conserving surgery.
  • For the breast-conserving surgery endpoint, there is no statistically significant difference between the treatment arms.
• Morbidity – Symptoms and health status
  • In the KEYNOTE 522 trial, the symptom-related endpoint was assessed using the EORTC QLQ-C30 and the EORTC QLQ-BR23. Health status was assessed in the KEYNOTE 522 study using the EQ-5D Visual Analogue Scale (VAS).
  • Consequently, no evaluable data are available for the endpoints of symptoms and health status.
• Quality of life – EORTC QLQ-C30 and EORTC QLQ-BR23
  • Consequently, there are no evaluable data available for the quality of life endpoint.
• Side effects – Adverse events (AEs)
  • In the KEYNOTE 522 trial, an adverse event occurred in 99.2% of premenopausal patients in the intervention arm and in 100% of those in the control arm.
• Side effects – Serious adverse events (SAEs) and discontinuation due to AEs
  • For the endpoints SAE, severe AEs and discontinuation due to AEs, a statistically significant disadvantage 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) compared with the appropriate comparator therapy.
• Side effects – severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe adverse events (AEs), no statistically significant difference was observed between the treatment groups.
• Overall assessment
  • In the mortality endpoint category, there was no statistically significant difference between the study arms for the endpoint of overall survival.
  • In the morbidity category, when considering relapses – operationalised via the relapse 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 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, also for the specific AEs.
  • On balance, the relevant advantage in terms of preventing recurrence is offset by disadvantages relating to side effects.
  • In a balanced assessment, the G-BA concludes that the advantage in terms of the endpoint of recurrence outweighs the disadvantages associated with side effects and that, overall, there is a moderate—and not merely minor—improvement in the 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, triple-negative breast cancer or early-stage triple-negative breast cancer with a high risk of recurrence, and a minor additional benefit was found.

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, triple-negative breast cancer or early-stage triple-negative breast cancer with a high risk of recurrence, additional benefit is not proven.
• No data are available to enable an assessment of the additional benefit.

Courtesy translation only, please refer to the German original.