Bosutinib (4) – Bosulif®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer presents the final results of the open-label, randomised and controlled BFORE trial, in which bosutinib was compared with the appropriate comparator therapy, imatinib, in the treatment of adults with newly diagnosed chronic myeloid leukaemia in the chronic phase.

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

• mortality
  • No statistically significant difference was observed between the treatment arms for the endpoint of overall survival.
  • An additional benefit of bosutinib over imatinib in terms of overall survival is therefore not proven.
  • Similar to the initial assessment, which was based on a data cut-off with a follow-up period of at least 24 months, even against the background of an overall survival rate under TKI therapy that is approximately equivalent to that of the general population, only a minor number of events occurred in both arms in the present final data set, which allowed for a minimum of 5 years’ follow-up of all patients.
• morbidity
  • Molecular response
  • Major molecular response (MMR) at 12 months was the primary endpoint of the BFORE study. For this endpoint, a statistically significant advantage was observed with bosutinib therapy compared with imatinib.
  • The endpoint is based on the molecular genetic detection of BCR-ABL transcripts in peripheral blood and is therefore based on haematological findings that are not directly relevant to patients.
  • No validation of MMR as a surrogate parameter for overall survival is available for the present assessment, even after the deadline has passed. The MMR endpoint is assessed neither as a patient-relevant endpoint nor as a validated surrogate endpoint and is therefore not taken into account for the present assessment.
  • 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.
  • No statistically significant difference was observed between the two treatment arms for this endpoint. Only a minor number of events occurred in both arms. An additional benefit of bosutinib compared with imatinib is therefore not proven.
  • Health status (EQ-5D Visual Analogue Scale)
  • Health status was assessed using the EQ-5D visual analogue scale. For the benefit assessment, the pharmaceutical manufacturer submitted responder analyses for the time to deterioration by ≥ 7 or ≥ 10 points from baseline, and by 15% of the scale range. These responder analyses for the three thresholds are used for the present benefit assessment.
  • The analyses show no statistically significant difference between the treatment arms in terms of time to deterioration.
  • Overall, therefore, an additional benefit of bosutinib over imatinib is not proven for the endpoint category of morbidity.
• quality of life
  • Health-related quality of life was assessed in the study using the Functional Assessment of Cancer Therapy – Leukaemia (FACT-Leu) questionnaire. This consists of four generic subscales measuring physical well-being (PWB), functional well-being (FWB), social well-being (SWB) and emotional well-being (EWB), as well as a leukaemia-specific subscale (FACT-Leu).
  • In the present analysis, the primary focus is on the FACT-Leu total score.
  • No significant difference was observed between the treatment arms for the endpoint of health-related quality of life as measured by the FACT-Leu total score.
  • An additional benefit of bosutinib over imatinib in terms of health-related quality of life is not proven.
• Side effects
  • Adverse events (AEs)
  • Overall, adverse events occurred in 98.8% of patients in the bosutinib arm and in 98.7% of patients in the imatinib arm.
  • Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment arms in terms of serious adverse events.
  • Severe AEs (CTCAE Grade 3 or 4)
  • With regard to severe adverse events of CTCAE grade ≥ 3, bosutinib showed a statistically significant disadvantage compared with imatinib.
  • Furthermore, there is an effect modification for the characteristic of age with regard to this endpoint. For both patients < 65 years and ≥ 65 years, a statistically significant disadvantage compared to bosutinib was observed in each group, albeit to varying extents, with patients ≥ 65 years being affected by severe AEs more frequently.
  • Discontinuation due to AEs
  • For the endpoint of therapy discontinuation due to an AE, a statistically significant disadvantage for bosutinib was observed.
  • The reliability of the findings for this endpoint is potentially limited due to possible competing events (reasons for discontinuation other than AEs, in particular disease progression).
  • Specific AEs
  • The IQWiG selected specific AEs based on the events occurring in the study, taking into account their frequency and differences between the treatment arms, as well as their relevance to patients.
  • When examining the specific AEs in detail, a statistically significant advantage for bosutinib over imatinib can be observed with regard to the specific AEs of eye diseases (SOC, AEs), oedema, peripheral (PT, AEs), musculoskeletal, connective tissue and bone disorders (SOC, AEs) and neutropenia (PT, severe AEs).
  • In contrast, bosutinib showed a statistically significant disadvantage with regard to specific AEs relating to gastrointestinal disorders (SOC, AEs), pruritus (PT, AEs), thrombocytopenia (PT, severe AEs), cardiac disorders (SOC, severe AEs) and elevated lipase (PT, severe AEs), diarrhoea (PT, severe AEs) and impaired liver function (CMQ, severe AEs).
  • In the overall analysis of side effect endpoints, bosutinib showed a statistically significant disadvantage with regard to severe AEs (CTCAE grade ≥ 3) and the endpoint ‘discontinuation due to AEs’. In detail, both advantages and disadvantages of bosutinib compared with imatinib can be identified for the specific adverse events. For serious adverse events, there is no statistically significant difference between the treatment arms. In the category of side effects, therefore, an overall disadvantage of bosutinib compared with imatinib is observed.

Courtesy translation only, please refer to the German original.