Fedratinib (1) – Inrebic®

• Clinical trials
  • The pharmaceutical manufacturer submitted data from the multicentre, open-label, single-arm, Phase II JAKARTA-2 trial for this patient population.

a) Adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, who have not been previously treated with a Janus-associated kinase (JAK) inhibitor, for the treatment of disease-related splenomegaly or symptoms

• mortality
  • The endpoint of overall survival was defined in the JAKARTA study as the time from randomisation to death or censoring.
  • Due to the premature termination of the trial, participants could not be followed up until death from any cause. Furthermore, the a priori planned analyses for these endpoints could not be carried out. Consequently, due to the clinical hold and the associated trial discontinuation, only post hoc analyses up to the end of treatment cycle 6 are available for overall survival.
  • Overall, the results regarding overall survival are of limited significance. Statistically, no difference is evident.
• morbidity
  • Spleen response assessed by MRI/CT; symptom response assessed by modified MSAF
  • In the JAKARTA trial, spleen response was the primary endpoint. This was defined as the proportion of patients with a ≥ 35 % reduction in spleen volume, as measured by MRI or CT at the end of cycle 6. Four weeks later, a repeat measurement was carried out using MRI/CT to confirm the spleen response rate of ≥ 35 %.
  • The modified MFSAF (Mylofibrosis Symptom Assessment Form) used to assess symptom response comprises six items relating to the disease-specific symptoms ‘night sweats’, ‘itching (pruritus)’, ‘abdominal discomfort’, ‘pain under the ribs on the left side’, ‘feeling of fullness, and bone or muscle pain’. The endpoint was operationalised as a reduction of ≥ 50% in the total symptom score (TSS).
  • Both in the analyses of spleen response without reconfirmation at 4 weeks and when taking reconfirmation at 4 weeks into account, a statistically significant advantage was observed for patients in the fedratinib arm.
  • At the same time, a statistically significant advantage was observed for patients treated with fedratinib in terms of symptom response as measured by the modified MFSAF, both in the symptom response rate – operationalised as a ≥ 50% reduction in the TSS at the end of cycle 6, as well as in the responder analyses, operationalised as time to an improvement of ≥ 50% compared with baseline.
  • EQ-5D-VAS
  • Health status was assessed in the JAKARTA study using the EuroQoL 5-Dimensional (EQ 5D) visual analogue scale. Higher scores indicate better health status.
  • There was no statistically significant difference between the two treatment arms in this respect. It should be noted, however, that the response rate in the comparator arm was below 70% and is therefore subject to uncertainty.
  • Overall, therefore, based on the advantage in terms of spleen volume reduction, combined with a concomitant advantage regarding symptom response in the morbidity category, a clinically relevant advantage can be identified.
• quality of life
  • No data on quality of life were collected in the JAKARTA study.
• Side effects
  • Analyses of the safety population were presented, in which adverse events were recorded up to 30 days after the end of cycle 6.
  • Serious adverse events (SAEs)
  • There was no statistically significant difference in the incidence of serious adverse events between the two treatment arms.
  • Severe adverse events, CTCAE grade ≥ 3
  • Severe side effects occurred at a statistically significantly higher rate with fedratinib than with placebo.
  • Therapy discontinuation due to AEs
  • There was no statistically significant difference in the incidence of therapy discontinuation due to AEs.
  • Adverse events of particular interest
  • There was a statistically significant disadvantage for fedratinib in the endpoint ‘time to first anaemia (CTCAE Grade 3/4)’ as well as a statistically significant advantage in favour of fedratinib for the endpoint ‘time to first secondary malignancy’.
  • Overall, therefore, in the category of side effects, there is a disadvantage associated with the more frequent occurrence of severe AEs (CTCAE grade ≥ 3) to the detriment of fedratinib.
• Overall assessment / Conclusion
  • For the benefit assessment of fedratinib in the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis, who have not been pre-treated with a Janus-associated kinase (JAK) inhibitor, the JAKARTA study provides data on mortality, morbidity and adverse events. The study was terminated prematurely due to the occurrence of Wernicke’s encephalopathy.
  • With regard to overall survival, due to the clinical hold and the associated study discontinuation, only post hoc analyses of overall survival up to the end of treatment cycle 6, with a short follow-up period, are available. Overall, the results on overall survival are of limited significance. Statistically, no difference is observed.
  • A statistically significant advantage can be observed for the endpoints of spleen response and symptom burden as assessed using the modified MFSAF. The advantage in spleen response, combined with an advantage in symptom response, is interpreted as a clear, clinically relevant improvement.
  • In the category of side effects, an overall disadvantage can be identified.
  • The overall assessment of additional benefit takes into account that the present JAKARTA study is subject to significant uncertainties and limitations. A particular source of uncertainty is the fact that the study had to be terminated prematurely due to cases of Wernicke’s encephalopathy. This results in a shortened follow-up period overall. No meaningful data are available for the endpoint of overall survival due to the premature termination of the study.
  • A further uncertainty regarding the study, which was conducted between 2012 and 2014, stems from the fact that, according to clinical experts, the comparator used in the study does not reflect the current standard of care in Germany.
  • The extent of the limitations and uncertainties described in the present study results is assessed, on balance, as so significant that, despite the substantial advantage in terms of morbidity, it does not permit an overall quantification of the additional benefit.

b) Adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who have been treated with ruxolitinib for the management of disease-related splenomegaly or symptoms

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification
• Overall, for fedratinib for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who have been treated with ruxolitinib, a non-quantifiable additional benefit has been identified, as the scientific evidence does not permit quantification.
• mortality
  • The overall survival endpoint was defined in the JAKARTA-2 study solely as an exploratory endpoint and operationalised as the time from the first dose to death or censoring.
  • Due to the premature termination of the trial, it was not possible to follow participants until death from any cause. Furthermore, the a priori planned analyses for this endpoint could not be carried out. The pharmaceutical manufacturer has submitted additional analyses for the benefit assessment.
  • Owing to the single-arm study design and the uncertainties in the analysis resulting from the early termination of the study, no conclusions regarding the extent of the additional benefit in the mortality category can be drawn from the results of the JAKARTA-2 study.
• morbidity
  • Spleen response assessed by MRI/CT; symptom response assessed by modified MSAF
  • In the JAKARTA-2 study, spleen response was the primary endpoint. This was defined as the proportion of patients with a reduction in spleen volume of ≥ 35%, measured by MRI or CT.
  • The modified MFSAF (Mylofibrosis Symptom Assessment Form) used to assess symptom response comprises six items relating to the disease-specific symptoms ‘night sweats’, ‘itching (pruritus)’, ‘abdominal discomfort’, ‘pain under the ribs on the left side’, ‘feeling of fullness, and bone or muscle pain’. The endpoint was operationalised as a reduction of ≥ 50% in the total symptom score (TSS).
  • It should be noted that a high proportion of patients were receiving a dosage that did not comply with the authorised regimen.
  • EORTC QLQ-C30
  • In the JAKARTA-2 study, symptoms were also assessed using the EORTC QLQ-C30 symptom scales (“fatigue”, “nausea and vomiting”, ‘Pain’, ‘Dyspnoea’, ‘Insomnia’, ‘Loss of appetite’, ‘Constipation’, ‘Diarrhoea’). Higher scores indicate severe symptoms. The endpoint was operationalised as the time to an improvement of ≥ 10 points.
  • Due to the single-arm study design, no conclusions regarding the extent of the additional benefit in the morbidity category can be drawn from the results of the JAKARTA-2 study.
• quality of life
  • EORTC QLQ-C30 functional scales
  • Quality of life was assessed in the JAKARTA-2 study using the EORTC QLQ-C30 functional scales. These comprise the scales ‘Global Health Status’, ‘Physical Functioning’, ‘Role Functioning’, ‘Emotional Functioning’, ‘Cognitive Functioning’ and ‘Social Functioning’. The endpoint was operationalised as the time to an improvement of ≥ 10 points, with higher scores indicating a better quality of life.
  • Due to the single-arm study design, no conclusions regarding the extent of the additional benefit in the quality of life category can be drawn from the results of the JAKARTA-2 study.
• Side effects
  • Total adverse events
  • An adverse event (AE) occurred in almost all patients. The results are presented for supplementary information only.
  • Serious adverse events (SAEs)
  • At least one serious adverse event (SAE) occurred in 26.8% of patients.
  • Severe adverse events, CTCAE grade ≥ 3
  • 60.8% of patients experienced severe adverse events (CTCAE grade ≥ 3).
  • Therapy discontinuation due to AEs
  • 13.4% of patients discontinued treatment due to an AE.
  • Adverse events of particular interest
  • The most common AEs of special interest were ‘Potential Wernicke’s encephalopathy’, ‘SMQ haemorrhages (narrow definition)’, ‘SMQ haemorrhages (broad definition)’, ‘heart failure/cardiomyopathy’, ‘anaemia, CTCAE grade 3 or 4’ and ‘thrombocytopenia’.
  • Due to the single-arm study design, no conclusions regarding the extent of the additional benefit in the category of side effects can be drawn from the results of the JAKARTA-2 study.
• Overall assessment / Conclusion
  • The assessment of the additional benefit of fedratinib for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis who were treated with ruxolitinib is based on the single-arm JAKARTA-2 study.
  • Results are available for patient-relevant endpoints in the categories of mortality, morbidity, quality of life and adverse events.
  • Due to the single-arm study design, a comparative assessment is not possible.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit based on the data presented are not possible.
• Overall assessment
  • In the overall review, for fedratinib in the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who have been treated with ruxolitinib, a non-quantifiable additional benefit is identified, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.