Bosutinib (2) – Bosulif®

Adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase (CP)

• An additional benefit is not proven for bosutinib in the treatment of adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase (CP).
• mortality
  • With regard to the endpoint of overall survival, no statistically significant difference was observed between the treatment arms (hazard ratio (HR) = 0.33 [0.09; 1.23], p-value 0.083).
  • However, up to the current data cut-off, only a minor number of events had occurred in both arms (3 (1.2%) vs. 9 (3.7%)).
  • Overall, the available results for the endpoint of overall survival are considered inconclusive.
  • An additional benefit of bosutinib over imatinib in terms of overall survival is not proven.
• Morbidity – progression to blast crisis
  • This endpoint is classified as patient-relevant, as progression to blast crisis is associated with a deterioration in the patient’s health status that is directly perceptible to the patient.
  • However, the pharmaceutical manufacturer has not submitted a separate analysis for this endpoint, but only an analysis of the ‘time to progression to an advanced stage of the disease’.
  • Consequently, no conclusion regarding additional benefit can be drawn on the basis of the submitted results on ‘time to progression to an advanced stage of the disease’. It is also not possible to draw conclusions regarding the endpoint ‘progression to blast crisis’.
• Morbidity – Health status according to the EQ-5D VAS
  • To assess health status, patients in the BFORE study were asked to complete the EQ-5D visual analogue scale (VAS).
  • The responder analyses show no significant difference between the treatment arms, neither when operationalised on the basis of a MID of 7 nor of 10 points.
  • An additional benefit of bosutinib is not proven for this endpoint.
• quality of life
  • Health-related quality of life is assessed in this study using the Functional Assessment of Cancer Therapy – Leukaemia (FACT-Leu) questionnaire.
  • The MMRM analyses show no statistically significant difference in health-related quality of life, as measured by the FACT-Leu total score, between the two treatment arms.
  • In addition, the results of the MMRM analyses of the subscales are presented, in which, consistently, no significant difference is observed.
  • An additional benefit of bosutinib for health-related quality of life is not proven.
• Side effects
  • Overall, adverse events occurred in 98.0% of patients in the bosutinib arm and in 96.3% of patients in the imatinib arm.
  • With regard to the endpoint of serious adverse events (SAEs), no statistically significant difference was observed between the two treatment groups.
  • A statistically significant disadvantage of bosutinib was observed in the time-to-event analyses for the endpoint of severe adverse events (CTCAE grade ≥ 3; HR = 1.63 [1.28; 2.07], p < 0.001). In the bosutinib arm, 65.4% of patients experienced severe adverse events (CTCAE grade ≥ 3), compared with 48.1% of patients in the imatinib arm.
  • In detail, bosutinib showed statistically significant disadvantages with regard to the endpoints ‘gastrointestinal disorders’ and ‘impaired liver function (CTCAE grade ≥ 3)’ among the specific adverse events.
  • Furthermore, statistically significant disadvantages were observed for the endpoints ‘diarrhoea (CTCAE grade ≥ 3)’, ‘elevated lipase (CTCAE grade ≥ 3)’, ‘rash’, ‘thrombocytopenia (CTCAE grade ≥ 3)’ and ‘cardiac disorders (CTCAE grade ≥ 3)’, although these were based on fewer events.
  • For the specific adverse events “musculoskeletal, connective tissue and bone disorders” and “oedema”, a statistically significant advantage was observed for bosutinib in each case.
  • With regard to the endpoint of discontinuation due to AEs, there was a statistically significant difference to the detriment of bosutinib (HR = 1.70 [1.06; 2.73], p = 0.025). 19.5% of patients discontinued treatment whilst on bosutinib, compared with 11.3% of patients on imatinib.
  • In the overall analysis of side effect endpoints, there was a statistically significant difference to the detriment of bosutinib with regard to severe side effects (CTCAE grade ≥ 3).
• Overall assessment
  • For the present benefit assessment of bosutinib for the treatment of adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase (CP), results from the randomised controlled Phase III BFORE trial are available for the endpoint categories of mortality, morbidity, quality of life and side effects, compared with the appropriate comparator therapy (imatinib).
  • The data on overall survival show no statistically significant difference between treatment with bosutinib and treatment with imatinib. However, an observation period of 24 months is considered too short to allow for a definitive assessment of overall survival in this therapeutic indication.
  • In the morbidity endpoint category, the available data also fail to demonstrate any additional benefit for bosutinib. The results on quality of life show no difference between the treatments.
  • The endpoints relating to side effects show a statistically significant disadvantage for bosutinib in terms of severe adverse events (CTCAE grade ≥ 3). With regard to specific adverse events, both advantages and disadvantages of bosutinib compared with imatinib can be identified. There is no statistically significant difference in serious adverse events (SAEs).
  • The disadvantages associated with severe adverse events of CTCAE grade ≥ 3, in particular liver toxicity, are considered relevant but not so severe as to justify a finding of ‘less benefit’ in the overall assessment of all endpoints.
  • In its overall assessment, the G-BA therefore concludes, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, that there is no evidence of an additional benefit of bosutinib for the treatment of adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in the chronic phase is not proven.

Courtesy translation only, please refer to the German original.