Belzutifan (1) – Welireg®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the LITESPARK 005 trial. This is an ongoing, open-label, randomised, multicentre Phase III trial in which belzutifan was compared with everolimus.

a) Adults with advanced clear-cell renal cell carcinoma who have received two or more prior treatments, including a PD-(L)1 inhibitor and at least two VEGF-targeted therapies, for whom everolimus represents the appropriate treatment on an individual patient basis

• Hint for a minor additional benefit
• Overall, a minor additional benefit is identified for belzutifan compared with everolimus, based on the advantages in terms of symptoms and therapy discontinuations due to adverse events.
• The certainty of the evidence is therefore classified as ‘hint’.
• mortality
  • In the LITESPARK 005 study, overall survival is defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• morbidity
  • PFS is defined as the time from randomisation to the first documented disease progression or to death from any cause, whichever occurs first.
  • For the PFS endpoint, there is a statistically significant advantage in favour of belzutifan compared with everolimus.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Symptoms are assessed in the LITESPARK 005 study using the EORTC QLQ-C30 and FKSI-DRS questionnaires.
  • Based on the EORTC QLQ-C30, statistically significant differences in favour of belzutifan were observed for the symptoms of insomnia, loss of appetite and diarrhoea, which are assessed as relevant advantages of belzutifan over everolimus.
  • Furthermore, a statistically significant advantage in favour of belzutifan is observed for the endpoint of pain.
  • For the symptom of pain, there is an effect modification by the characteristic ‘age’. For individuals aged ≥ 65 years, the subgroup analyses reveal a statistically significant advantage for belzutifan. For individuals aged < 65 years, however, no statistically significant difference was observed between the treatment groups.
  • Based on the FKSI-DRS, statistically significant advantages in favour of Belzutifan compared with everolimus can be identified for disease symptoms.
  • Overall, within the morbidity endpoint category, Belzutifan demonstrates relevant advantages in the symptoms of insomnia, loss of appetite and diarrhoea, as well as an advantage in terms of pain (EORTC QLQ-C30). Furthermore, there is an advantage of belzutifan over everolimus in terms of disease symptoms (FKSI-DRS).
  • Even when taking into account the clinical relevance of the aforementioned symptoms in this therapeutic indication, the advantage of belzutifan in the morbidity endpoint category is not assessed as higher than ‘minor’ overall.
• Health-related quality of life
  • Health-related quality of life is assessed in the LITESPARK 005 study using the EORTC QLQ-C30 questionnaire, and analyses are presented for the time to first deterioration.
  • There is no statistically significant difference between the treatment groups.
  • However, for the social functioning scale, there is an effect modification by the characteristic ‘age’. For individuals aged ≥ 65 years, the subgroup analyses reveal a statistically significant advantage for belzutifan. For individuals aged < 65 years, by contrast, there is no statistically significant difference between the treatment groups.
• Side effects
  • AE occurred in almost all patients in both study arms.
  • There were no statistically significant differences between the treatment groups for the endpoints SAE and severe AEs.
  • A statistically significant difference in favour of the belzutifan arm was observed for therapy discontinuations due to AEs, with an effect modification observed for the ‘age’ characteristic.
  • For participants aged ≥ 65 years, the subgroup analyses revealed a statistically significant advantage for belzutifan. For participants aged < 65 years, however, there was no statistically significant difference between the treatment groups.
  • In detail, statistically significant differences in favour of belzutifan compared with everolimus were observed for infections and parasitic diseases (severe AEs), stomatitis (AEs), fever (AEs), disorders of the skin and subcutaneous tissue (AEs), as well as fatigue (severe AE) and hyperglycaemia (severe AE).
  • Conversely, belzutifan has disadvantages compared with everolimus in terms of the endpoints of hypoxia (severe AE), constipation (AE) and dizziness (AE).
  • An overall analysis of the results regarding side effects shows that belzutifan has an advantage over everolimus in terms of therapy discontinuations due to AEs. In detail, there are advantages and disadvantages for specific AEs.
• Overall assessment
  • The results for the overall survival endpoint show no statistically significant difference between the treatment groups.
  • In the morbidity endpoint category, there are significant advantages regarding the symptoms of insomnia, loss of appetite and diarrhoea, as well as further positive effects for the symptom of pain (assessed using the EORTC QLQ-C30) and disease-related symptoms (assessed using the FKSI-DRS).
  • With regard to health-related quality of life, there are no statistically significant differences between the treatment groups.
  • In the ‘side effects’ endpoint category, an advantage for belzutifan was observed in terms of therapy discontinuations due to AEs. In detail, advantages and disadvantages were observed for specific AEs.
  • Across all endpoints, effect modifications due to the characteristic ‘age’ were observed for the endpoints of pain, social functioning and therapy discontinuations due to AEs. For individuals aged ≥ 65 years, the subgroup analyses reveal a statistically significant advantage for belzutifan. For individuals aged < 65 years, however, no statistically significant difference was observed between the treatment groups.
  • In the overall assessment of the available results for patient-relevant endpoints, a minor additional benefit for belzutifan in the treatment of adults with advanced clear cell renal cell carcinoma following two or more therapy discontinuations due to adverse events lines of prior therapy, comprising a PD-(L)1 inhibitor and at least two VEGF-targeted therapies, and for whom everolimus represents the appropriate treatment on an individual basis, compared with everolimus.

b) Adults with advanced clear-cell renal cell carcinoma following two or more prior treatments comprising a PD-(L)1 inhibitor and at least two VEGF-targeted therapies, for whom axitinib, cabozantinib, lenvatinib in combination with everolimus or sunitinib represents the individually appropriate treatment

• The additional benefit is not proven.
• No data were provided for comparison with axitinib, cabozantinib, lenvatinib in combination with everolimus or sunitinib.
• No additional benefit has been demonstrated for belzutifan in the treatment of adults with advanced clear cell renal cell carcinoma following two or more prior therapies comprising a PD-(L)1 inhibitor and at least two VEGF-targeted therapies, and for whom axitinib, cabozantinib or lenvatinib in combination with everolimus or sunitinib represents the appropriate treatment on an individual patient basis, there is no proof that it is the appropriate treatment compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.