Ripretinib (1) – Qinlock®

• Clinical trials
  • The benefit assessment is based on the results of the randomised, double-blind, placebo-controlled Phase III trial INVICTUS.
  • The trial compares ripretinib in combination with best supportive care (BSC) against placebo and BSC (hereinafter: ripretinib versus placebo).

Adults with advanced gastrointestinal stromal tumours (GIST) who have previously received treatment with three or more kinase inhibitors, including imatinib

• mortality
  • In the INVICTUS trial, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed in favour of ripretinib compared with placebo.
  • The extent of the prolongation in overall survival achieved is regarded as a very significant improvement.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the INVICTUS study. It is defined as the time (in weeks) from randomisation to the first confirmed disease progression or death from any cause.
  • PFS is statistically significantly prolonged with ripretinib compared with placebo.
• quality of life
  • Health-related quality of life is assessed in the INVICTUS trial using the functional scales and the global health status scale (overall assessment) of the cancer-specific EORTC QLQ-C30 questionnaire.
  • In the stratified analysis of time to first deterioration by ≥ 10 points, no statistically significant difference was observed between the treatment arms for the endpoints of cognitive functioning, emotional functioning and social functioning.
  • With regard to the endpoints of physical functioning and role functioning, a statistically significant advantage was observed in favour of ripretinib compared with placebo.
  • For the endpoint of global health status, however, a statistically significant disadvantage was observed compared with placebo for ripretinib.
  • For this reason, no conclusions are drawn from the results on global health status for the assessment of health-related quality of life.
  • Overall, for the quality of life endpoint category, two positive effects were observed for ripretinib regarding the physical functioning and role functioning endpoints; given the advanced stage of the disease and treatment and the magnitude of the observed effects, these are considered to be of high significance despite the uncertainties.
• Side effects
  • The analysis of the results on side effects is based on the double-blind phase of the safety population.
  • Adverse events (AEs) were reported by almost all participants in the ripretinib arm (98.8%) and in the placebo arm (97.7%).
  • Severe AEs (CTCAE grade ≥ 3) occurred in 55.3% of participants in the ripretinib arm and in 51.2% in the placebo arm.
  • Serious adverse events (SAEs) occurred in 34.1% of participants in the ripretinib arm and 44.2% in the placebo arm.
  • AE leading to therapy discontinuation occurred in 7 subjects (8.2%) in the ripretinib arm and 5 subjects (11.6%) in the placebo arm.
  • The pharmaceutical manufacturer presented post-hoc event time analyses in the dossier. These show a statistically significant difference in favour of ripretinib compared with placebo for both the endpoints of serious AEs and severe AEs.
  • No statistically significant difference was observed for the endpoint ‘discontinuation due to AEs’.
  • Given the differences in treatment and observation periods between the study arms, event time analyses generally constitute appropriate evaluations.
  • For these reasons, there is considerable uncertainty regarding the interpretation of the results based on the presented analyses of AEs.
  • Taking into account that this study compares an active, anti-tumour therapy with placebo, and given the small number of patients who discontinued treatment due to AEs, an overall therapeutic advantage is assumed with regard to the side effects of ripretinib.
  • Against this background, it is not possible to quantify the available results in the ‘side effects’ endpoint category to determine the extent of the additional benefit; the results can only be interpreted to a limited extent.
• Overall assessment / Conclusion
  • For the endpoint of overall survival, there is a statistically significant difference in favour of ripretinib in combination with best supportive care (BSC) compared with placebo in combination with BSC. The extent of the effect is assessed as a very marked improvement.
  • In the overall assessment of the morbidity endpoint category, the symptoms recorded show neither advantages nor disadvantages for ripretinib compared with placebo. In contrast, for the health status endpoint, there is a clear advantage for treatment with ripretinib.
  • For the quality of life endpoint category, clear advantages are evident in the physical functioning and role functioning endpoints.
  • Taking into account the advanced stage of the disease and treatment, as well as the magnitude of these effects, the advantages in terms of morbidity and health-related quality of life are considered to be of great significance, despite the existing uncertainties.
  • With regard to side effects, there are considerable uncertainties concerning the presented analyses of adverse events (AEs). Given the advanced stage of the disease, it can be assumed that a major proportion of progression events or events corresponding to the symptoms of the underlying disease were recorded in both study arms and included in the analyses of AEs.
  • Taking into account that this study compares an active, anti-tumour therapy with a placebo, and given the small number of patients who discontinued treatment due to AEs, Ripretinib is generally considered to have a favourable side-effect profile.
  • In its overall assessment, the G-BA concludes that, given the extent of the prolongation in survival and in view of the available results on the patient-reported endpoints of health status, physical functioning and role functioning, as well as the endpoints of severe AEs and SUEs, which collectively support the additional benefit, ripretinib is found to provide a previously unattained significant improvement in treatment-related benefit within its therapeutic indication, particularly given the advanced stage of treatment and the associated poor prognosis for patients.

Courtesy translation only, please refer to the German original.