Pembrolizumab (16) – Keytruda®

• Clinical trials
  • The KEYNOTE 361 trial is an ongoing Phase III trial being conducted at 172 trial centres in 21 countries.

Adults with locally advanced or metastatic urothelial carcinoma who are not suitable for cisplatin-based therapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥ 10; first-line

• Additional benefit is not proven for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are not suitable for cisplatin-based therapy and whose tumours express PD-L1 with a combined positive score (CPS) of ≥ 10.
• mortality
  • overall survival
  • Overall survival was the primary endpoint of the KEYNOTE 361 trial. No statistically significant difference was observed between the treatment groups for this endpoint.
• morbidity
  • Symptoms
  • The symptom-related endpoints were assessed using the EORTC QLQ-C30 symptom scales. For the endpoints of breathlessness, fatigue, nausea and vomiting, diarrhoea, pain, insomnia and constipation, no statistically significant difference was observed between the treatment groups in any case. For the endpoint of loss of appetite, a statistically significant disadvantage was observed compared to pembrolizumab.
  • Given the only minor effect observed for the loss of appetite endpoint, no overall disadvantage is inferred for the ‘symptoms’ endpoint.
  • health status
  • The health status endpoint was assessed using the EQ-5D VAS. No statistically significant difference was observed for health status (EQ-5D VAS).
  • Progression-free survival
  • The progression-free survival endpoint was assessed in the study; however, it was not presented in the dossier for the patient population considered in the benefit assessment.
• quality of life
  • EORTC QLQ-C30
  • Health-related quality of life was assessed using the functional scales of the EORTC QLQ-C30. No statistically significant difference was observed between the treatment groups for any of the endpoints: global health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning.
• Side effects
  • Endpoints in the side effect category were recorded for the duration of treatment with the study medication plus 30 days (for AEs and severe AEs) or up to 90 days (for serious AEs).
  • Total adverse events (AEs)
  • Almost all study participants experienced an adverse event. These are presented here for information purposes only.
  • Serious adverse events (SAEs)
  • There were no statistically significant differences between pembrolizumab and chemotherapy for the SAE endpoint.
  • Severe AEs (CTCAE grade ≥ 3)
  • For the endpoint of severe AEs (CTCAE grade 3 or higher), a significant advantage in favour of pembrolizumab was observed. The rate of severe AEs is high in both treatment groups (72.7% for pembrolizumab vs. 88.7% for chemotherapy). In the pembrolizumab arm, severe AEs occurred at a median of 2.5 months later than in the chemotherapy arm.
  • Discontinuation due to AEs, immune-mediated SAE and severe AEs (CTCAE grade ≥ 3)
  • There were no statistically significant differences between the study arms for the endpoints of discontinuation due to AEs, immune-mediated SAEs and immune-mediated severe AEs (CTCAE grade ≥ 3).
  • Specific AE
  • For gastrointestinal disorders (SOC, AEs) and disorders of the blood and lymphatic system (SOC; severe AEs, CTCAE grade ≥ 3), pembrolizumab showed a statistically significant advantage over combination therapy with carboplatin and gemcitabine.
  • For the specific adverse events of metabolic and nutritional disorders (SOC, severe AEs, CTCAE grade ≥ 3) and vascular disorders (SOC, severe AEs, CTCAE grade ≥ 3), a statistically significant difference in favor of pembrolizumab compared with chemotherapy can be observed.
• Overall assessment
  • For the re-assessment of the benefits of pembrolizumab for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are unsuitable for cisplatin-based therapy and whose tumours express PD-L1 with a combined positive score (CPS) of ≥ 10, results on mortality, morbidity, health-related quality of life and side effects are available from the KEYNOTE 361 trial.
  • In the overall analysis of the available results for patient-relevant endpoints, a statistically significant improvement is observed only in the area of side effects, based on the positive effect in one endpoint: severe AEs (CTCAE grade ≥ 3). By contrast, no relevant differences between the treatments were observed in terms of overall survival, symptoms, health status or health-related quality of life.
  • Against this background, the present positive effect on side effects is not considered sufficient to establish, overall, a relevant and not merely minor improvement in treatment-related benefit.
  • As a result of a balancing assessment, the G-BA therefore concludes that, for pembrolizumab as monotherapy for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are not suitable for cisplatin-based therapy and whose tumours express PD-L1 with a combined positive score (CPS) of ≥ 10, additional benefit is not proven.

Courtesy translation only, please refer to the German original.