Ruxolitinib (3) – Jakavi®

• Clinical trials
  • To demonstrate the additional benefit of ruxolitinib, the pharmaceutical manufacturer submitted the pivotal RESPONSE trial.
  • A total of 222 patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea were enrolled in this multicentre, open-label, randomised, controlled, parallel-group trial in a 1:1 ratio.
  • The study investigated the efficacy and safety of ruxolitinib compared with BAT (Best Available Therapy).

Patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea therapy

• Hint of considerable additional benefit.
• The G-BA classifies the extent of the additional benefit of ruxolitinib as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• The certainty of the finding (probability of additional benefit) is classified as ‘hint’.
• mortality
  • overall survival
  • In the RESPONSE trial, no deaths occurred in either treatment arm.
  • Given the slow progression of the disease and the short follow-up period, the study’s statistical power regarding this endpoint is limited.
  • Furthermore, as the majority of patients in the comparator arm switched to the ruxolitinib arm as early as week 32, the statistical significance of the results collected at later time points is also extremely limited.
  • Consequently, the results from the later assessment time points cannot be used for the present benefit assessment.
  • In the endpoint category of mortality, an additional benefit of ruxolitinib over the appropriate comparator therapy is therefore not proven.
• Morbidity – haematocrit control, no indication for phlebotomy
  • With regard to the individual component ‘haematocrit control, no indication for phlebotomy’ of the combined primary study endpoint ‘haematocrit control whilst remaining free of phlebotomy and achieving a reduction in spleen volume of ≥ 35%’, there was a statistically significant difference in favour of ruxolitinib (60% vs. 19.6%; RR: 2.70; 95% CI: [1.87; 3.90]; p < 0.001).
  • Control of the haematocrit level and the resulting absence of an indication for phlebotomy are clinically relevant for patients in this therapeutic indication.
  • Phlebotomies are associated with a reduction in patients’ quality of life and an increased risk of treatment-related side effects.
• Morbidity – reduction in spleen volume by ≥ 35%
  • Treatment with ruxolitinib resulted in a reduction in spleen volume of at least 35% in a significantly higher proportion of patients in the RESPONSE trial (38.2% vs. 0.9%; RR: 42.76; 95% CI: [5.99; 305.31]; p < 0.001).
  • A sustained reduction in pathologically enlarged spleen volume, combined with a reduction in debilitating symptoms that is noticeable to the patient and an improvement in quality of life, is clinically relevant.
• Morbidity – Thromboembolic events
  • The endpoint ‘thromboembolic events’ was operationalised in the RESPONSE trial using the SMQ term ‘embolic and thrombotic events’.
  • At week 32, there was no statistically significant difference between the two study arms with regard to thromboembolic events (RR: 0.17; 95% CI: [0.02; 1.37]; p = 0.120).
• Morbidity – Disease transformation
  • Disease transformation was defined as a transition to acute leukaemia or myelofibrosis.
  • In the ruxolitinib arm, this event occurred in three patients, compared with one patient in the control arm.
  • The difference between the two study arms is not statistically significant (RR: 3.03; 95% CI: [0.32; 28.66]; p = 0.326).
• Morbidity – Health status (PGI-C)
  • General health status was assessed using the patient-reported questionnaire ‘Patients’ Global Impression of Change’.
  • This revealed a statistically significant difference in favour of ruxolitinib.
  • At week 32, a total of 91.5% of patients in the ruxolitinib arm reported an improved health status (much better, better or slightly better), compared with 35.9% of patients in the control arm.
  • A deterioration in health status (slightly worse or much worse) was reported by 1.1% (ruxolitinib arm) and 18.5% (comparator arm) of patients, respectively.
• Health-related quality of life – General quality of life or overall health status (EORTC-QLQ-C30)
  • With regard to general quality of life or overall health status, there was a statistically significant difference in favour of ruxolitinib at the Week 32 assessment (RR: 3.53; 95% CI: [2.12; 5.88]; p < 0.001).
• Side effects – Dyspnoea
  • Dyspnoea occurred statistically significantly more frequently during treatment with ruxolitinib than with the appropriate comparator therapy (10.0% vs. 1.8%; RR: 5.55; 95% CI: [1.26; 24.46]; p = 0.010).
  • In contrast, the results for the symptom of dyspnoea, as assessed using the EORTC-QLQ-C30 questionnaire, showed an advantage of ruxolitinib.
  • The differing directions of effect observed across the two endpoint categories complicate the interpretation of the data relating to this event.
• Conclusion
  • Advantages of ruxolitinib were observed in the morbidity endpoint category through an improvement in general health status, a reduction in phlebotomies due to improved haematocrit control, a reduction in spleen volume associated with a decrease in debilitating symptoms of the disease, an improvement in the morbidity endpoints of fatigue and loss of appetite, and in the quality of life endpoint category with regard to overall health status and physical functioning.
  • However, due to the short study duration, long-term data are lacking on thromboembolic events relevant to patients, on cardiovascular and overall mortality, and on side effects.
  • However, when the available results on mortality, morbidity and quality of life, together with the findings on side effects, are considered as a whole, ruxolitinib does not demonstrate a sustained and, compared with the appropriate comparator therapy, previously unattained significant improvement in treatment-related benefit – in particular, no cure of the disease, no major prolongation of life, no long-term freedom from severe symptoms and no substantial avoidance of serious side effects.
  • Therefore, classification as ‘major additional benefit’ is not justified.

Courtesy translation only, please refer to the German original.