Pembrolizumab (19) – Keytruda®

• Clinical trials
  • KEYNOTE 775/309 is a multicentre, open-label, randomised controlled trial comparing pembrolizumab in combination with lenvatinib against standard of care therapy, with a choice of doxorubicin or paclitaxel.

Adult female patients with advanced or recurrent endometrial cancer who have experienced disease progression during or following prior platinum-based therapy, at any stage of the disease, for whom curative surgical treatment or radiotherapy is not an option

• Consequently, the G-BA has determined that pembrolizumab + lenvatinib provides an indication of considerable additional benefit compared with the appropriate comparator therapy.
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • In the KEYNOTE 775/309 study, overall survival is defined as the time from randomisation to death, regardless of the underlying cause of death.
  • For the endpoint of overall survival, a statistically significant difference was observed in favour of pembrolizumab in combination with lenvatinib.
  • This prolongation of survival time achieved by treatment with pembrolizumab in combination with lenvatinib, compared with treatment with the appropriate comparator therapy, is regarded as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • In the KEYNOTE 775/309 study, progression-free survival is defined as the time from randomisation to disease progression (assessed according to RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged in the intervention arm compared with the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories.
  • This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life is assessed in the KEYNOTE 775 study / 309 using the symptom scales of the disease-specific EORTC QLQ-C30 questionnaire and the disease-specific supplementary module for endometrial cancer, EORTC QLQ-EN24.
  • For the endpoints of emotional functioning and social functioning, a statistically significant advantage was observed in favour of pembrolizumab in combination with lenvatinib in each case.
  • The 95% confidence interval for the SMD did not lie entirely outside the irrelevance range of −0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically relevant.
  • For the endpoint ‘negative body image’, a statistically significant advantage was observed in favour of pembrolizumab in combination with lenvatinib.
  • The 95% confidence interval for the SMD lay entirely outside the non-significant range of −0.2 to 0.2. This is interpreted as a significant effect.
  • No usable data were available for the endpoint of sexual enjoyment, as only 18.2% of patients were included in the analysis.
  • For all other endpoints, no statistically significant difference was observed between the study arms.
  • Overall, a significant difference between the treatments was observed for only a single endpoint: a positive effect on the ‘negative body image’ endpoint.
  • Given the various aspects of health-related quality of life that were assessed in the study using the EORTC QLQ-C30 and EORTC QLQ-EN24 questionnaires, this single effect is not considered sufficient to conclude that there has been an overall improvement in health-related quality of life.
• Side effects – Adverse events (AEs)
  • In the KEYNOTE 775/309 study, AEs occurred in almost all patients in both study arms.
  • The results are presented here for supplementary information only.
• Overall assessment
  • Data on mortality, morbidity, quality of life and side effects are available from the open-label, randomised, controlled KEYNOTE 775 / 309 trial for the benefit assessment of pembrolizumab in combination with lenvatinib.
  • For the endpoint of overall survival, there is a statistically significant difference in favour of pembrolizumab in combination with lenvatinib. The extent of the effect is assessed as a marked improvement.
  • With regard to symptoms (assessed using the EORTC QLQ-C30 and -EN24), the treatment with pembrolizumab in combination with lenvatinib showed positive effects on the endpoints of dyspnoea, lymphoedema, tingling/numbness, changes in taste and hair loss, as well as a negative effect with regard to the endpoint of diarrhoea.
  • In terms of symptoms, there is an overall advantage of pembrolizumab in combination with lenvatinib.
  • With regard to health status (assessed using the EQ-5D VAS), neither positive nor negative effects were observed.
  • For health-related quality of life (assessed using the EORTC QLQ-C30 and -EN24), there is no improvement when all results are considered as a whole.
  • In terms of side effects, pembrolizumab in combination with lenvatinib is associated with disadvantages regarding serious AEs and therapy discontinuations due to AEs.
  • With regard to severe AEs, there are no statistically significant differences between the study arms.
  • In detail, pembrolizumab in combination with lenvatinib predominantly showed negative AEs.
  • Overall, there is a clear improvement in overall survival. Furthermore, there are predominantly advantages in terms of symptom relief. This is offset by disadvantages regarding serious AEs and therapy discontinuations due to AEs.
  • Consequently, a considerable additional benefit is identified for pembrolizumab in combination with lenvatinib compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.