Enfortumab Vedotin (2) – Padcev®

• Clinical trials
  • The EV-302 / KN-A39 trial is a randomised, controlled, open-label Phase III trial, which included a total of 886 patients with histologically confirmed urothelial carcinoma of the bladder, renal pelvis, the ureter or the urethra, and were randomly assigned 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 enfortumab vedotin + pembrolizumab compared with cisplatin + gemcitabine.
  • Similarly, in the presented sensitivity analyses 1 and 3 – in which patients in the comparator arm for whom maintenance therapy with avelumab might have been indicated, but who died without receiving such therapy, were treated differently – a statistically significant advantage in favour of enfortumab vedotin + pembrolizumab compared with cisplatin + gemcitabine is observed in each case.
  • This effect is not maintained when the maximum assumption is made that all these patients in the comparator arm would have survived up to the current data cut-off (sensitivity analysis 2).
  • Overall, the results for overall survival are interpreted as 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 can be identified, the extent of which cannot be quantified with certainty 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 was statistically significantly prolonged with enfortumab vedotin + pembrolizumab 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.
  • For the endpoints ‘global health status’, ‘role functioning’, ‘emotional functioning’ and ‘cognitive functioning’, no statistically significant difference was observed between the treatment groups in any case.
  • For the endpoint ‘physical functioning’, there was no statistically significant difference between the treatment groups. However, there is an effect modification for the characteristic of age. For patients aged < 65 years, there is a statistically significant advantage in favour of enfortumab vedotin + pembrolizumab; for patients aged ≥ 65 years, there is no statistically significant advantage.
  • For the endpoint ‘social functioning’, there is no statistically significant difference between the treatment groups. There are effect modifications for the characteristics of age and metastases, which cannot be assessed.
  • Given that the effect modifications described are only evident for individual endpoints, the result for the overall population is used for the assessment.
  • Overall, no differences relevant to the benefit assessment were found for the endpoint category ‘health-related quality of life’.
• Side effects – severe adverse events (CTCAE Grade 3–4)
  • For the endpoint of severe adverse events, there is a statistically significant advantage in favour of enfortumab vedotin + pembrolizumab.
• Overall assessment
  • For the assessment of the additional benefit of enfortumab vedotin in combination with pembrolizumab 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 from the randomised, open-label, multicentre, controlled EV-302/KN-A39 trial. 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. 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 can be interpreted with regard to the endpoint of overall survival – despite the uncertainties described – and used for the assessment of additional benefit.
  • For the overall survival endpoint, the main analysis and the submitted sensitivity analyses 1 and 3 show a statistically significant difference in favour of enfortumab vedotin + pembrolizumab compared with cisplatin + gemcitabine.
  • Overall, the results for overall survival are assessed as 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 Item 3 and Items 9a–9g, EORTC QLQ-C30, EQ-5D VAS), there are moderate advantages in favour of enfortumab vedotin + pembrolizumab compared with cisplatin + gemcitabine.
  • For health-related quality of life (assessed using the EORTC QLQ-C30), there is no overall difference relevant to the benefit assessment.

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 enfortumab vedotin in combination with pembrolizumab for the first-line treatment of adults with unresectable or metastatic urothelial carcinoma 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 within the current data set.
  • The primary analysis shows a statistically significant difference in favour of enfortumab vedotin + pembrolizumab compared with carboplatin + gemcitabine.
  • The three sensitivity analyses presented also each show a statistically significant advantage for enfortumab vedotin + pembrolizumab compared with carboplatin + gemcitabine. This effect is also maintained in sensitivity analysis 2, which is based on the maximum assumption that all patients in the comparator arm would have survived up to the current data cut-off.
  • Overall, the results for overall survival are interpreted as a marked improvement.
• Morbidity – Progression-free survival
  • Progression-free survival was defined in the EV-302 / 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 was statistically significantly prolonged with enfortumab vedotin + pembrolizumab compared with carboplatin + 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.
  • No statistically significant differences were observed between the treatment groups in any of the functional scales.
  • For the endpoints ‘role functioning’ and ‘emotional functioning’, there is an effect modification by the characteristic of sex. For women, there is a statistically significant advantage in each case for enfortumab vedotin + pembrolizumab; for men, there is no statistically significant advantage in either case.
  • Given that the effect modifications shown only occur for individual endpoints, the results for the overall population are used for the assessment.
  • Overall, there are no differences relevant to the benefit assessment for the ‘health-related quality of life’ endpoint category.
• Side effects – severe adverse events (CTCAE Grade 3–4)
  • For the endpoint of severe adverse events, there is a statistically significant advantage in favour of enfortumab vedotin plus pembrolizumab.
• Overall assessment
  • For the assessment of the additional benefit of enfortumab vedotin in combination with pembrolizumab 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 that is not suitable for cisplatin-based therapy are available 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. 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 the three sensitivity analyses presented show a statistically significant difference in favour of enfortumab vedotin + pembrolizumab compared with carboplatin + gemcitabine.
  • Overall, the results for overall survival are assessed 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 in favour of enfortumab vedotin + pembrolizumab compared with carboplatin + 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 ‘side effects’ endpoint category, enfortumab vedotin + pembrolizumab shows an advantage in terms of severe side effects, whilst, when examined in detail, there are both advantages and disadvantages for individual specific side effects.
  • Overall, the G-BA concludes that enfortumab vedotin in combination with pembrolizumab for the first-line treatment of adults with unresectable or metastatic urothelial carcinoma offers a considerable additional benefit compared with carboplatin + gemcitabine (followed, where appropriate, by avelumab maintenance therapy).

Courtesy translation only, please refer to the German original.