Fedratinib (2) – Inrebic®

b) Adults with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis who have been treated with ruxolitinib for the treatment of disease-related splenomegaly or symptoms

• Hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• The certainty of the evidence for the identified additional benefit is classified as ‘hint’.
• mortality
  • The overall survival endpoint is defined as the time from randomisation to death, regardless of the cause of death. There is no statistically significant difference between the treatment arms.
• Morbidity – spleen response assessed by MRI/CT
  • In the FREEDOM2 study, spleen response was the primary endpoint. The spleen response rate was defined as the proportion of participants with a ≥ 35 % reduction in spleen volume, measured by magnetic resonance imaging (MRI) or computed tomography (CT), at week 24 compared with baseline. A significant advantage was observed in the fedratinib arm.
• Morbidity – Conclusion on splenic response and symptomatic response using MFSAF
  • A sustained reduction in pathologically enlarged spleen volume, combined with a reduction in debilitating disease symptoms that is noticeable to patients, is considered clinically relevant. In this study, spleen response was assessed using imaging procedures. The continuous analyses for the MFSAF-TSS show a statistically significant difference in favour of fedratinib; however, no clinical relevance can be inferred from this.
  • Consequently, no difference relevant to the benefit assessment can be inferred with regard to symptoms; for this reason, splenic response is presented only as a supplementary finding for the primary endpoint of the FREEDOM2 trial.
• quality of life
  • Quality of life in patients was assessed in the FREEDOM2 study using the EORTC QLQ-C30. Please refer to the comments above regarding the ‘symptoms’ endpoint.
  • The available data from the EORTC QLQ-C30 cannot be analysed.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants. The results are presented here only as supplementary information.
• Overall assessment
  • For the re-benefit assessment of fedratinib following the expiry of the authorisation period for adults with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis who had been treated with ruxolitinib, data are available from the FREEDOM2 trial, in which fedratinib was compared with best available therapy (BAT). Results from this study are available on mortality, morbidity, quality of life and adverse events.
  • For the endpoint of overall survival, there was no statistically significant difference between the treatment arms.
  • In the morbidity endpoint category, results are available for spleen response, symptom response (assessed using the MFSAF), symptoms (EORTC QLQ-C30) and health status (EQ-5D VAS).
  • For spleen response, assessed using imaging procedures (MRI/CT), a statistically significant difference in favour of fedratinib was observed. With regard to symptom response as assessed by MFSAF, the available continuous analyses show a statistically significant difference in favour of fedratinib. A sustained reduction in pathologically enlarged spleen volume, combined with a noticeable reduction in debilitating disease symptoms for patients, is considered clinically relevant. The 95% confidence interval of the standardised mean difference (Hedges’ g) of the MFSAF-TSS lies within the irrelevance threshold (-0.2 to 0.2), meaning that it cannot be concluded that the observed effect in symptom response as measured by MFSAF is clinically relevant. Consequently, no relevant difference can be identified with regard to symptoms.
  • No suitable data are available on symptoms (assessed using the EORTC QLQ-C30) and health status (assessed using the EQ-5D-VAS) due to an excessively high proportion of missing values. This also applies to the data on health-related quality of life (assessed using the EORTC QLQ-C30).
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the morbidity data.
  • With regard to side effects, there is a statistically significant disadvantage for fedratinib in terms of severe side effects (CTCAE grade ≥ 3). There are no statistically significant differences for severe side effects or discontinuation due to side effects. In detail, there are also disadvantages for individual adverse events of particular interest.
  • For the endpoint category of side effects, a disadvantage for fedratinib is observed overall.
  • Overall, for fedratinib in the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis who have been treated with ruxolitinib, as the scientific evidence does not permit quantification of the additional benefit.

Courtesy translation only, please refer to the German original.