Ruxolitinib (1) – Jakavi®

• Clinical trials
  • The COMFORT I trial is a randomised, two-arm, blinded, placebo-controlled Phase III trial.
  • COMFORT II is a randomised, two-arm, open-label, (active) controlled Phase III trial.
  • In each of the study arms, ruxolitinib was administered at doses ranging from 30 to 50 mg daily.
  • In the control arm of the COMFORT II trial, the best available therapy (BAT), as determined by the investigator, was used.

Adult patients with primary myelofibrosis (PMF), post-polycythaemia vera myelofibrosis (post-PV-MF) or post-essential thrombocythemia myelofibrosis (post-ET-MF)

• For the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of ruxolitinib as minor, 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.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a reduction in non-serious symptoms of the disease (the ‘morbidity’ endpoint) is achieved.
• mortality
  • The ‘overall survival’ endpoint was assessed as a secondary endpoint in both registration trials.
  • The studies were not designed for this purpose, and the sample sizes are insufficient to demonstrate differences in overall survival.
  • At the time of assessment of the primary endpoint, there was no statistically significant difference between the groups in terms of overall survival in either study.
  • After this point, patients in the comparator arm were permitted to switch to ruxolitinib (crossover).
  • The intention-to-treat (ITT) analyses presented for this purpose show statistically significant results in favour of ruxolitinib for the COMFORT I trial and, at the time of the last data collection, also for the COMFORT II trial; however, due to numerous limitations (e.g. high crossover rate to ruxolitinib, high lost-to-follow-up rate, unclear censoring) and, given their minor statistical power, present a high potential for bias.
  • Nor did the additional analyses on overall survival submitted by the manufacturer as part of the consultation procedure (Sirulnik et al. 2013) serve to support the validity of the results on overall survival.
  • There are therefore no meaningful data available for the endpoint ‘overall survival’ to assess the extent of the additional benefit.
• Morbidity – reduction in spleen volume and disease symptoms
  • The median baseline spleen volume was approximately 2500 ml across all studies and groups.
  • In both studies, the ruxolitinib groups showed a comparable reduction in spleen volume of a median of approximately 30%.
  • 41.9% (COMFORT I, after 24 weeks) and 28.5% (COMFORT II, after 48 weeks) of ITT ruxolitinib patients, respectively, achieved a reduction in spleen volume of at least 35% (“responders”).
  • In addition, the COMFORT I study assessed disease symptoms for seven individual symptoms: ‘night sweats/hot flushes’, ‘itching’, ‘upper abdominal discomfort’, ‘pain under the ribs’, ‘feeling of fullness (early satiety)’, ‘bone and muscle pain’ and ‘inactivity’ were recorded and evaluated individually using the patient questionnaire ‘Myelofibrosis Symptoms Assessment Form, Version 2.0’ (MFSAF v2.0) and evaluated individually; they were also – excluding the ‘inactivity’ symptom – combined into a total score (Total Symptom Score, TSS).
  • A statistically significant reduction was demonstrated in both the individual symptom scores of the MFSAF v2.0 and the TSS total score.
  • Neither of these assessment tools has yet been sufficiently validated; consequently, the interpretability of the data—for both the MFSAF v2.0 and the TSS—can only be assessed to a limited extent.
  • Nevertheless, the results of the MFSAF v2.0 questionnaire were included in the resolution to illustrate possible effects on the individual symptoms of the condition.
  • A long-lasting reduction in the pathologically enlarged spleen volume, combined with a reduction in debilitating disease symptoms that is noticeable to the patient, is of relevance to patients.
  • With regard to the ‘morbidity’ endpoint, the G-BA assesses the extent of the minor additional benefit of ruxolitinib.
  • This represents a moderate – and not merely minor – improvement in treatment-related benefit that has not been achieved previously, as a reduction in the non-serious symptoms of the disease – ‘night sweats/feeling of heat’, ‘itching’, ‘upper abdominal discomfort’, ‘pain under the ribs’, ‘feeling of fullness (premature satiety)’, ‘bone and muscle pain’ and ‘inactivity’.
• Quality of life – EORTC QLQ-C30
  • Data from the oncology-specific, cross-disease patient questionnaire EORTC QLQ-C30 are available for both studies to assess the additional benefit in terms of quality of life.
  • Analyses are available for the ‘Overall Health/Quality of Life Status’ subscale, as well as for some subscales that differ between the studies.
  • Apart from the fatigue subscale (see morbidity), no data on the validity of the subscales are available.
  • Consequently, based on the data collected using the EORTC QLQ-C30 questionnaire, as well as the minor response rate to the questionnaires (COMFORT II) and the imbalances between the study arms (COMFORT I, II), no valid conclusions can be drawn regarding the extent of the additional benefit for the endpoint ‘quality of life’.
• Side effects
  • The positive effects of ruxolitinib are offset by adverse events.
  • The proportion of patients who experienced at least one adverse event was comparable across studies and treatment groups.
  • The proportions were also comparable for serious adverse events and for study discontinuations due to adverse events.
  • 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.
  • 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, in the G-BA’s assessment, lead to a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.