Pembrolizumab (28) – Keytruda®

• Clinical trials
  • KEYNOTE 826 is an ongoing, multicentre, double-blind, randomised controlled trial comparing pembrolizumab in combination with chemotherapy, with or without bevacizumab, against placebo in combination with chemotherapy, with or without bevacizumab.

a1) Adult female patients with persistent, recurrent or metastatic cervical cancer whose tumours express PD-L1 with a CPS ≥ 1; First-line — pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab

• Consequently, the G-BA concludes that pembrolizumab, in combination with cisplatin and paclitaxel with or without bevacizumab, or in combination with carboplatin and paclitaxel with or without bevacizumab, for the treatment of persistent, recurrent or metastatic cervical cancer with PD-L1-expressing tumours (CPS ≥ 1) in adults.
• Consequently, the certainty of evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab, compared with the control arm.
  • The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • In the KEYNOTE 826 trial, the PFS endpoint is defined as the time from randomisation to the first documented occurrence of disease progression or death from any cause, whichever occurs first.
  • There is a statistically significant advantage for pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-CX24)
  • For the symptoms of dyspnoea and peripheral neuropathies, there are statistically significant disadvantages compared with pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab, compared with the controlarm.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • A statistically significant advantage in favour of pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab, was observed for the health status endpoint compared with the control arm.
• morbidity
  • Overall, no net advantage or disadvantage was identified for the morbidity endpoint category, based on an advantage in health status and disadvantages in the symptoms of dyspnoea and peripheral neuropathies.
• Health-related quality of life
  • No statistically significant difference was observed between the treatment arms with regard to health-related quality of life.
  • No usable data are available for the ‘sexual enjoyment’ subscale of the EORTC QLQ-CX24 due to an excessively high proportion of missing values at the start of the study.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all patients. The results for the endpoint ‘total adverse events’ are presented for supplementary information only.
• Side effects – Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3)
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE and severe AEs (CTCAE grade ≥ 3).
• Side effects – Therapy discontinuation due to AEs
  • For the endpoint ‘therapy discontinuations due to AEs’ (discontinuation of at least one active component), there was a statistically significant difference in favor of pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab.
• Side effects – Specific AEs
  • For the specific SAE – immune-mediated SAE, severe immune-mediated SAE (CTCAE grade ≥ 3) and disorders of the skin and subcutaneous tissue (severe SAE, CTCAE grade ≥ 3), there is a statistically significant difference in favor of pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab.
• Side effects
  • An overall review of the results regarding side effects shows that, for pembrolizumab in combination with cisplatin and paclitaxel, with or without bevacizumab, or in combination with carboplatin and paclitaxel, with or without bevacizumab, compared with placebo in combination with cisplatin and paclitaxel with or without bevacizumab, or in combination with carboplatin and paclitaxel with or without bevacizumab, compared with placebo in combination with cisplatin and paclitaxel with or without bevacizumab, or in combination with carboplatin and paclitaxel with or without bevacizumab, a higher rate of therapy discontinuation due to AEs. In detail, there are disadvantages regarding specific AEs.
• Overall assessment
  • In its overall assessment of the available results on patient-relevant endpoints, the G-BA concludes that the significant advantage in overall survival outweighs the disadvantage in terms of therapy discontinuations due to adverse events. There is a significant improvement in treatment-related benefit that has not been achieved previously.

a2) Adult female patients with persistent, recurrent or metastatic cervical cancer whose tumours express PD-L1 with a CPS ≥ 1; First-line — pembrolizumab in combination with chemotherapies other than cisplatin and paclitaxel, with or without bevacizumab, or carboplatin and paclitaxel, with or without bevacizumab

• No data are available to enable an assessment of the additional benefit. The additional benefit is therefore not proven.

b) Adult female patients with persistent, recurrent or metastatic cervical cancer whose tumours express PD-L1 with a CPS ≥ 1; following first-line chemotherapy and for whom further antineoplastic therapy is an option

• There are no data available to enable an assessment of the additional benefit. The additional benefit is therefore not proven.

Courtesy translation only, please refer to the German original.