Ruxolitinib (2) – Jakavi®

• Clinical trials
  • To demonstrate the additional benefit of ruxolitinib, the pharmaceutical manufacturer submitted the COMFORT-I and COMFORT-II trials.
  • A total of 309 patients (155 in the ruxolitinib arm and 154 in the placebo arm) with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.
  • In the open-label, randomised Phase III COMFORT-II trial, the efficacy and safety of ruxolitinib used in accordance with the summary of product characteristics (146 patients) were compared with best-available therapy selected by the clinician (Best-Available-Therapy; 73 patients).

Adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis

• Mortality – Overall survival
  • In the COMFORT-I trial, overall survival was assessed as a secondary endpoint at pre-specified time points following a treatment duration of at least 24 weeks (primary analysis) or at least 144 weeks (3-year analysis).
  • Both analyses showed a numerical but statistically non-significant advantage of ruxolitinib plus best supportive care (BSC) compared with BSC alone (primary analysis: HR 0.67 [95% CI: 0.30; 1.50]; 3-year analysis: HR 0.69 [95% CI: 0.46; 1.03]).
  • A statistically significant advantage of ruxolitinib was observed in the post hoc interim analyses conducted in March 2011 (HR 0.50 [95% CI: 0.25; 0.98], p = 0.040) and in April 2013 (HR 0.67 [95% CI: 0.45; 1.00], p = 0.047).
  • For the endpoint of overall survival, neither the primary analysis nor the planned 3-year analysis showed a statistically significant effect in favour of ruxolitinib in terms of reducing the risk of mortality.
  • However, the results from supplementary analyses of the data cuts dated 1 March 2011 and 5 April 2013 show (p = 0.040 and p = 0.047, respectively) significant results in favour of ruxolitinib.
  • Due to the high proportion of patients who switched treatments, any survival benefit from ruxolitinib may well be underestimated, as the effects of ruxolitinib treatment are also included in the control arm of the study due to the analysis methodology.
  • Nevertheless, there is major uncertainty regarding the overall survival results due to the inconsistent significance observed at different analysis time points.
  • The a priori defined analyses, which are therefore more meaningful, show no statistically significant difference between the treatment arms.
• Morbidity – Leukaemia-free survival
  • The endpoint ‘leukaemia-free survival’ is a composite endpoint comprising components relating to mortality and morbidity (leukaemic transformation).
  • For the mortality endpoint category, this endpoint is assessed as an unvalidated surrogate.
  • Given its composition and the lack of presentation of the results for the individual components of this endpoint, its relevance to patients is questionable, and it should not be taken into account when assessing the additional benefit of ruxolitinib.
  • Furthermore, for the patient-relevant morbidity component ‘leukaemic transformation’ – as is the case for the composite endpoint – there are no statistically significant differences between the treatment groups in the COMFORT-I trial.
• Health-related quality of life – EORTC QLQ-C30
  • Data from the oncology-specific, cross-disease patient questionnaire EORTC QLQ-C30 are available for assessing the additional benefit in terms of health-related quality of life.
  • Due to imbalances between the study arms (a difference of approximately 20% between the intervention arm and the control arm in terms of the questionnaires taken into account), no valid conclusions regarding quality of life can be drawn based on the analysis method presented in the dossier (without a replacement strategy).
  • The LOCF (last observation carried forward) analysis submitted as part of the commenting procedure takes this circumstance into account and may be used for the assessment.
  • This results in a statistically significant and relevant difference in favour of ruxolitinib for the global health status scale and for all functional scales, with the exception of cognitive functioning.
  • The advantages in terms of health-related quality of life support the findings in favour of ruxolitinib for the morbidity endpoints.
• Side effects
  • The positive effects of ruxolitinib are offset by adverse events.
  • The proportion of patients who experienced adverse events was comparable across groups.
  • The proportions were also comparable for serious adverse events and for study discontinuations due to adverse events.
  • Overall, however, the results regarding the overall rates cannot be evaluated, as symptoms of the underlying disease were also recorded to a large extent and it is not possible to distinguish with sufficient certainty between treatment-related adverse events and adverse events caused by the underlying disease.
  • The European Medicines Agency (EMA) describes the following side effects as being of particular interest for ruxolitinib: myelosuppressive side effects, in particular thrombocytopenia and anaemia, and resulting complications, in particular infections and bleeding.
  • These events are also typical of the untreated condition, but occur more frequently with ruxolitinib.
  • Furthermore, disorders of the nervous system (by system organ class) occur significantly more frequently with ruxolitinib (36.8% vs. 23.8%).
  • Overall, the side effects are classified as significant for patients, but predominantly as manageable and treatable.
  • In particular, taking into account the current severity of the disease and the lack of treatment options, these significant side effects do not lead to a downgrading of the extent of the additional benefit in the G-BA’s assessment.
• Overall assessment
  • An overall assessment of the results regarding mortality, morbidity, quality of life and side effects indicates that, for ruxolitinib compared with the appropriate comparator therapy in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit that has not been achieved to date, with regard to the morbidity endpoint category, taking into account the results on overall survival, supported by an advantage in health-related quality of life.
  • On the basis of these considerations, the information contained in the dossier, the results of the benefit assessment and the statements submitted, the G-BA concludes that ruxolitinib offers considerable additional benefit.

Courtesy translation only, please refer to the German original.