Pembrolizumab (14) – Keytruda®

• Clinical trials
  • To demonstrate the additional benefit of pembrolizumab compared with the appropriate comparator therapy, the pharmaceutical manufacturer has submitted results from the randomised, actively controlled, open-label KEYNOTE 204 trial comparing pembrolizumab with brentuximab vedotin.
  • The KEYNOTE 051 trial is an open-label, single-arm Phase 1/2 trial investigating pembrolizumab as monotherapy in children and adolescents with various oncological indications.

a1) Adult patients with relapsed or refractory classical Hodgkin’s lymphoma following failure of an autologous stem cell transplant (autologous stem cell transplant) or following at least two prior lines of treatment, where autologous stem cell transplant is not an option and for whom brentuximab vedotin constitutes the appropriate treatment as determined by the treating physician.

• Taking the available results into account as a whole, the G-BA recommends pembrolizumab for the treatment of adult patients with relapsed or refractory classical Hodgkin’s lymphoma following failure of an autologous stem cell transplant (auto-HSCT) or following at least two prior lines of treatment, where auto-HSCT is not an option and for whom brentuximab vedotin constitutes the appropriate treatment as determined by a doctor, the G-BA has established that pembrolizumab offers considerable additional benefit compared with brentuximab vedotin.
• Overall, for these reasons, the certainty of the evidence for the established additional benefit is classified as a hint.
• mortality
  • No data were available in the dossier for the endpoint of overall survival; consequently, the mortality rate was considered as a substitute for the benefit assessment.
  • With regard to overall mortality, there is no statistically significant difference between the treatment groups in the overall population.
  • To date, the proportion of patients who have died is very small; final analyses for the overall survival endpoint are still pending.
• Morbidity – Health status (EQ-5D VAS)
  • For patients in the KEYNOTE 204 trial, there was no statistically significant difference between the treatment groups for either a decrease in the score of ≥ 7 points or ≥ 10 points.
  • With regard to the health status endpoint, there is therefore neither an advantage nor a disadvantage for pembrolizumab.
• Morbidity – Symptoms
  • For the endpoints of fatigue, pain and loss of appetite, a statistically significant advantage was observed in the relevant patient population, favouring pembrolizumab over brentuximab vedotin.
  • Overall, whilst the certainty of the evidence is limited, there are in some cases large positive effects on individual endpoints.
• Morbidity – B-symptoms
  • For the endpoint ‘time to first occurrence of at least one B-symptom’, no significant difference was observed between the treatment groups in the relevant patient population.
  • With regard to the endpoint ‘B-symptoms’, there is therefore neither an advantage nor a disadvantage for pembrolizumab.
• Health-related quality of life
  • For the endpoints of global health status, physical functioning, emotional functioning, and role functioning, a statistically significant advantage was observed in favour of pembrolizumab compared with brentuximab vedotin.
  • For the endpoint of cognitive functioning, no statistically significant difference was observed between the study arms.
  • Overall, in the quality of life category, treatment with pembrolizumab showed consistent and, in some cases, substantial positive effects across several endpoints, albeit with limited certainty of the findings.
  • Pembrolizumab offers a clear advantage over treatment with brentuximab vedotin in terms of health-related quality of life.
• Side effects – severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe adverse events (CTCAE grade ≥ 3), a statistically significant advantage was observed in favour of pembrolizumab compared with brentuximab vedotin in the relevant patient population.
  • Although a statistically significant advantage for pembrolizumab over brentuximab vedotin can be observed in terms of severe AEs (CTCAE grade ≥ 3); this advantage is, however, insufficient in terms of its effect size to establish a difference relevant to the benefit assessment for the entire endpoint category.
• Side effects – severe adverse events (SAEs) and discontinuation due to adverse events (AEs)
  • For the endpoints of severe adverse events (SUEs) and discontinuation due to adverse events (UEs), no statistically significant difference was observed between the treatment groups in the relevant patient population.
• Side effects – Immune-mediated severe adverse events (immune-mediated SUEs, CTCAE grade ≥ 3)
  • For the endpoint of immune-mediated SUEs, as well as for immune-mediated severe AEs, no statistically significant difference was observed between the treatment groups.
• Overall assessment
  • With regard to mortality, neither an advantage nor a disadvantage can be identified for pembrolizumab compared with brentuximab vedotin. To date, the proportion of patients who have died is very small; final analyses for the overall survival endpoint are still pending.
  • In the morbidity category, positive effects of treatment with pembrolizumab were observed for the endpoints of fatigue, pain and loss of appetite. These are assessed overall as a marked improvement in symptoms.
  • With regard to health-related quality of life, positive effects of treatment with pembrolizumab were observed for the endpoints of global health status, emotional functioning, social functioning, and physical functioning, and role functioning. These are assessed overall as a marked improvement in health-related quality of life.
  • For the endpoint category of side effects, there was no statistically significant difference between the study arms in terms of serious side effects (AEs), discontinuations due to AEs, the endpoint of immune-mediated severe side effects (SUEs), or immune-mediated severe AEs. With regard to severe adverse events (CTCAE grade ≥ 3), there is a statistically significant advantage in favour of pembrolizumab compared with brentuximab vedotin. However, in terms of its effect size, this advantage is insufficient to establish a difference relevant to the benefit assessment for the endpoint category as a whole. Consequently, no relevant advantage or disadvantage can be identified for pembrolizumab compared with brentuximab vedotin in this endpoint category.
  • The overall assessment takes into account that there are significant advantages of pembrolizumab compared with brentuximab vedotin in the endpoint categories of morbidity and quality of life.

a2) Adult patients with relapsed or refractory classical Hodgkin’s lymphoma following failure of an autologous stem cell transplant (autologous stem cell transplant) or following at least two previous lines of treatment, where autologous stem cell transplant is not an option and for whom brentuximab vedotin is not considered the appropriate treatment according to medical judgement.

• The additional benefit is not proven.
• For the assessment of the additional benefit of pembrolizumab compared with the appropriate comparator therapy in adult patients with relapsed or refractory classical Hodgkin’s lymphoma following failure of an autologous stem cell transplant (auto-HSCT) or following at least two previous lines of treatment, where auto-HSCT is not an option and for whom brentuximab vedotin is not considered the appropriate treatment according to medical judgement, no data are available.

b) Children and adolescents aged 3 years and over with relapsed or refractory classical Hodgkin lymphoma following failure of an autologous stem cell transplant (auto-SCT) or following at least two prior lines of treatment, where auto-SCT is not an option

• The additional benefit is not proven.
• The specific implementation of the evidence transfer by the pharmaceutical manufacturer is not considered appropriate, as the appropriate comparator therapy specified by the G-BA for children and adults is not identical with regard to the use of Brentuximab Vedotin.
• In the KEYNOTE 204 trial in adult patients with relapsed or refractory classical Hodgkin lymphoma, brentuximab vedotin monotherapy was used as the comparator. According to the statements made by the medical societies during the oral hearing, brentuximab vedotin monotherapy is not a suitable appropriate comparator therapy for children in the specified therapeutic indication. Instead, brentuximab vedotin should only be used in combination with suitable chemotherapeutic agents for children in this therapeutic indication. Consequently, the appropriate comparator therapy for the adult and paediatric populations differs with regard to the medicinal product brentuximab vedotin. It is therefore not possible to extrapolate evidence from the adult study to the paediatric population.
• Pembrolizumab may represent a relevant treatment option for paediatric patients in individual cases within the indicated therapeutic indication.

Courtesy translation only, please refer to the German original.