Pembrolizumab (36) – Keytruda®

• Clinical trials
  • The EV-302/KN-A39 trial is a randomised, controlled, open-label Phase III trial involving a total of 886 patients with histologically confirmed urothelial carcinoma of the bladder, renal pelvis, the ureter or the urethra, and were randomised in a 1:1 ratio to receive treatment with enfortumab vedotin in combination with pembrolizumab (N = 442) or cisplatin or carboplatin in combination with gemcitabine (N = 444).

a) Adults with unresectable or metastatic urothelial carcinoma who are eligible for cisplatin-based therapy; first-line treatment

• mortality
  • In the EV-302 / KN-A39 study, overall survival was defined as the time from randomisation to death from any cause.
  • Taking into account the sensitivity analyses presented, it is possible to interpret the results for the overall survival endpoint within the current data set.
  • The primary analysis shows a statistically significant difference in favour of pembrolizumab + enfortumab vedotin compared with cisplatin + gemcitabine.
  • The three sensitivity analyses presented also each show a statistically significant advantage in favour of pembrolizumab + enfortumab vedotin compared with cisplatin + gemcitabine.
  • Overall, the results for overall survival are considered to represent a relevant improvement. However, the results of the main analysis and the three sensitivity analyses presented on overall survival differ significantly in terms of the extent of the respective effect. Therefore, an additional benefit for the endpoint of overall survival is identified, the extent of which cannot be reliably quantified overall.
• Morbidity – Progression-free survival
  • Progression-free survival was defined in the EV-302 study / KN-A38 as the time from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first, assessed in accordance with RECIST (Response Evaluation Criteria in Solid Tumours, Version 1.1) criteria, version 1.1, by a blinded, independent, central review committee.
  • PFS is statistically significantly prolonged with pembrolizumab + enfortumab vedotin compared with cisplatin + gemcitabine (followed, where applicable, by avelumab maintenance therapy).
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• Health-related quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed using the EORTC QLQ-C30 questionnaire and operationalised as the time to the first deterioration of ≥ 10 points.
  • In the functional scales, there was no statistically significant difference between the treatment groups for the endpoints ‘global health status’, ‘role functioning’, ‘emotional functioning’ and ‘cognitive functioning’.
  • No statistically significant differences were observed between the treatment groups for the endpoints ‘physical functioning’ and ‘social functioning’.
  • However, there is an effect modification for the characteristic of age. For patients aged < 65 years, there is a statistically significant advantage (‘physical functioning’) or no statistically significant difference (‘social functioning’); whilst for patients aged 65 years or older, there is no statistically significant difference (‘physical functioning’) or a statistically significant disadvantage (‘social functioning’) associated with pembrolizumab + enfortumab vedotin compared with the appropriate comparator therapy.
  • Given that this effect modification is only evident for individual endpoints, the result for the overall population is used for the assessment.
  • Overall, there are no differences relevant to the benefit assessment in the health-related quality of life endpoint category.
• Side effects – Total adverse events (AEs)
  • In the EV-302/KN-A39 study, AEs occurred in almost all patients in both treatment arms. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of pembrolizumab in combination with enfortumab vedotin in adults with unresectable or metastatic urothelial carcinoma in the first-line setting, results on mortality, morbidity, health-related quality of life and side effects from the randomised, open-label, multicentre, controlled study EV-302/KN-A39. The assessment is based on the relevant patient population that is suitable for cisplatin-based therapy.
  • In the EV-302/KN-A39 study, maintenance therapy with avelumab was not routinely planned for patients in the comparator arm who were progression-free following chemotherapy, in accordance with the study protocol. Further data and sensitivity analyses are available, in which patients who did not receive avelumab despite being eligible according to the pharmaceutical manufacturer’s criteria and who subsequently died are taken into account in various ways. Based on the information provided regarding the implementation of maintenance therapy with avelumab and the associated sensitivity analyses, the study results for the endpoint of overall survival can be interpreted – despite the uncertainties described – and used for the assessment of additional benefit.
  • For the overall survival endpoint, the main analysis and each of the three sensitivity analyses presented show a statistically significant advantage in favour of pembrolizumab + enfortumab vedotin compared with cisplatin + gemcitabine.
  • Overall, the results for overall survival are considered to represent a relevant improvement. However, the results of the main analysis and the three sensitivity analyses presented for overall survival differ significantly in terms of the extent of the respective effect. Consequently, an additional benefit for the endpoint of overall survival is identified, the extent of which is non-quantifiable overall.
  • With regard to the endpoint category of morbidity (assessed using BPI-SF items 3 and 9a–9g, EORTC QLQ-C30, EQ-5D VAS), there are moderate advantages in favour of pembrolizumab + enfortumab vedotin compared with cisplatin + gemcitabine.
  • For health-related quality of life (assessed using the EORTC QLQ-C30), there is overall no difference relevant to the benefit assessment.
  • For the endpoint category of side effects, pembrolizumab + enfortumab vedotin shows an advantage in terms of severe side effects, whilst, in detail, there are both advantages and disadvantages for individual specific side effects.

b) Adults with unresectable or metastatic urothelial carcinoma who are not suitable for cisplatin-based therapy; first-line treatment

• Overall, the G-BA concludes that pembrolizumab + enfortumab vedotin offers a considerable additional benefit compared with carboplatin + gemcitabine (followed, where appropriate, by avelumab maintenance therapy).
• The certainty of evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • In the EV-302 / KN-A39 trial, overall survival was defined as the time from randomisation to death from any cause.
  • Taking into account the sensitivity analyses presented, it is possible to interpret the results for the overall survival endpoint based on the available data.
  • The primary analysis shows a statistically significant difference in favour of pembrolizumab + enfortumab vedotin compared with carboplatin + gemcitabine.
  • The three sensitivity analyses presented also each show a statistically significant advantage in favour of pembrolizumab + enfortumab vedotin compared with carboplatin + gemcitabine.
  • Overall, the results regarding overall survival are interpreted as a marked improvement.
• Morbidity – Progression-free survival
  • Progression-free survival was defined in the EV-302 study / KN-A39 as the time from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first, assessed in accordance with RECIST (Response Evaluation Criteria in Solid Tumours, version 1.1) criteria, version 1.1, by a blinded, independent, central review committee.
  • PFS is statistically significantly prolonged with pembrolizumab in combination with enfortumab vedotin compared with carboplatin in combination with gemcitabine (followed, where applicable, by avelumab maintenance therapy).
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• Health-related quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed using the EORTC QLQ-C30 questionnaire and operationalised as the time to the first deterioration of ≥ 10 points.
  • For the endpoints ‘global health status’, ‘physical functioning’ and ‘cognitive functioning’, no statistically significant difference was observed between the treatment groups.
  • For the endpoint ‘role functioning’, a statistically significant advantage was observed in favour of pembrolizumab + enfortumab vedotin compared with carboplatin + gemcitabine, whilst for the endpoints ‘emotional functioning’ and ‘social functioning’, respectively, no statistically significant difference was observed between the treatment groups.
  • However, for the endpoints mentioned, there is an effect modification by the characteristic of sex. For women, there is a statistically significant advantage in favour of pembrolizumab + enfortumab vedotin in each case; for men, there is no statistically significant difference in any case.
  • Given that the effect modifications described are only evident for individual endpoints, the results for the overall population are used for the assessment.
  • Overall, no differences relevant to the benefit assessment were found for the health-related quality of life endpoint category.
• Side effects – Total adverse events (AEs)
  • In the EV-302/KN-A39 study, AEs occurred in almost all patients in both treatment arms. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of pembrolizumab in combination with enfortumab vedotin in adults with unresectable or metastatic urothelial carcinoma in the first-line setting, the results on mortality, morbidity, health-related quality of life and side effects for the relevant patient population of patients who are not suitable for cisplatin-based therapy, from the randomised, open-label, multicentre, controlled study EV-302/KN-A39.
  • In the EV-302/KN-A39 study, maintenance therapy with avelumab was not routinely planned for patients in the comparator arm who were progression-free following chemotherapy, in accordance with the study protocol. Further data and sensitivity analyses are available, in which patients who did not receive avelumab despite being eligible according to the pharmaceutical manufacturer’s criteria and who subsequently died are taken into account in various ways. Based on the information provided regarding the implementation of maintenance therapy with avelumab and the associated sensitivity analyses, the study results for the endpoint of overall survival can be interpreted – despite the uncertainties described – and used for the assessment of additional benefit.
  • For the overall survival endpoint, the main analysis and each of the three sensitivity analyses presented show a statistically significant advantage in favour of pembrolizumab + enfortumab vedotin compared with cisplatin + gemcitabine.
  • Overall, the results for overall survival are interpreted as a clear improvement.
  • With regard to the morbidity endpoint category (assessed using BPI-SF Item 3 and Items 9a–9g, EORTC QLQ-C30, EQ-5D VAS), there are moderate advantages for pembrolizumab + enfortumab vedotin compared with carboplatin + gemcitabine (followed, where applicable, by avelumab maintenance therapy).
  • For health-related quality of life (assessed using the EORTC QLQ-C30), there is overall no difference relevant to the benefit assessment.
  • For the endpoint category of side effects, pembrolizumab + enfortumab vedotin shows an advantage in terms of severe side effects, a disadvantage in terms of treatment discontinuation due to side effects, and, in detail, both advantages and disadvantages for individual specific side effects.
  • Overall, the G-BA concludes that pembrolizumab plus enfortumab vedotin offers a considerable additional benefit compared with carboplatin plus gemcitabine (followed, where appropriate, by avelumab maintenance therapy).

c) Adults with unresectable or metastatic urothelial carcinoma who are not suitable for cisplatin- and carboplatin-based therapy; first-line treatment

• The additional benefit is not proven.
• Reasoning: For first-line treatment of adults with unresectable or metastatic urothelial carcinoma who are not suitable for cisplatin- and carboplatin-based therapy, the pharmaceutical manufacturer has not submitted any data for the assessment of additional benefit.

Courtesy translation only, please refer to the German original.