Bosutinib (1) – Bosulif®

• Clinical trials
  • The assessment of the extent of the additional benefit of bosutinib is based on the 200 WW study. This study is a multicentre, single-arm, open-label Phase I/II trial.

Adults with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase (CP), accelerated phase (AP) and blast crisis (BC), who have been pre-treated with at least one tyrosine kinase inhibitor and for whom imatinib, nilotinib and dasatinib are not considered suitable treatment options

• In summary, the extent of the additional benefit of bosutinib is assessed as follows: For adults with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase (CP), accelerated phase (AP) and blast crisis (BC), who have been pre-treated with at least one tyrosine kinase inhibitor and for whom imatinib, nilotinib and dasatinib are not considered suitable treatment options, there is an additional benefit, but it is non-quantifiable because the available scientific evidence does not currently permit this.
• The G-BA classifies the extent of the additional benefit of bosutinib as non-quantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• In the present case and for this indication, the low number of patients in the target population and the absence of a control group in the study are relevant to the decision. Consequently, a quantitative comparative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data provided.
• mortality
  • The endpoint ‘overall survival’ was evaluated for the target population. In the CP, 6 patients (40 %) died during second-line therapy and 5 patients (23.8 %) during third- or fourth-line therapy; in the AP, there were 3 (60 %) deaths, and in the BK, 9 (81.8 %) deaths. No data are available on median overall survival in the target population. There is no control group. The scientific data therefore do not permit a quantification of the extent of the additional benefit of bosutinib in terms of mortality.
• Morbidity – Cytogenetic Response (CyR)
  • The primary endpoint of the 200 WW study was major cytogenetic response (Major Cytogenetic Response, MCyR) at week 24 in imatinib-resistant Ph+ CML patients in the CP group who had received no tyrosine kinase inhibitor other than imatinib as prior treatment (CP-CML second-line therapy). The dossier reported the cumulative MCyR, defined as the proportion of patients who achieved an MCyR at any time during treatment.
  • Five of the 15 patients in the CP-CML second-line cohort of the registration population achieved an MCyR as their best response whilst on bosutinib, including four who achieved a complete cytogenetic response (CCyR). According to the data in the dossier, a further 4 patients achieved a response deeper than CCyR, such as a complete molecular response (CMR) or a major molecular response (MMR). These patients are not counted here amongst the responders in terms of MCyR, as achieving an MMR usually, but not necessarily, also entails achieving an MCyR or CCyR.
  • Of the 21 patients with CML in the CP who, following failure of imatinib and an additional second-generation tyrosine kinase inhibitor and for whom the administration of a further tyrosine kinase inhibitor was not considered a suitable treatment option, 6 patients achieved an MCyR as their best response, including 4 patients who achieved a CCyR. Two out of five patients in the AP group and two out of 11 patients in the BK group achieved a CCyR as their best response.
  • However, it is not possible to draw conclusions regarding the extent of the additional benefit, particularly due to the minor number of cases but also because of the lack of a control group.
• Morbidity – Molecular Response (MR)
  • Cumulative major molecular response was defined as the proportion of patients who achieved an MMR at any time during treatment or who were able to maintain an MMR present at the start of the study. Overall, only a minor number of cases are available regarding MMR for the target population.
  • Four of the 15 patients (26.7%) in the second-line control group and three of the 21 patients (14.3%) in the third- and fourth-line control group achieved an MMR. One patient in the AP group (20%) achieved a CMR whilst on bosutinib and was able to maintain this until the data cut-off at 92 weeks without discontinuing treatment. No patient in the BK group achieved an MMR.
  • Particularly due to the minor number of cases, but also because of the lack of a control group, no conclusions can be drawn regarding the extent of the additional benefit.
• quality of life
  • However, no usable data on quality of life are available for the target population.
• Side effects
  • The positive effects of bosutinib are offset by adverse events. In the 200 WW study, 100% of patients experienced at least one adverse event. The most common adverse events in the target population were gastrointestinal events (92.3 per cent), including, in particular, diarrhoea in 40 patients (76.9 per cent) and nausea in 22 patients (42.3 per cent), disorders of the blood and lymphatic system in 25 patients (48.1%), including, in particular, thrombocytopenia in 15 patients (28.8 %), and general disorders and administration site conditions in 16 patients (30.8 %), in particular fever in 14 patients (26.9 %).
  • At least one serious adverse event occurred in 28 patients (53.8 %), in particular cardiac events in 11 patients (21.2 %) and infections in 10 patients (19.2 %). CTCAE Grade 3 and 4 adverse events occurred in 36 patients (69.2%), most commonly disorders of the blood and lymphatic system in 18 patients (34.6%). Thirteen patients (25.0%) discontinued treatment with bosutinib due to adverse events. The most common reasons were: cardiac events in 4 patients (7.7 %), elevated liver enzyme levels in 2 patients (3.8 %), and thrombocytopenia and neutropenia in 2 patients (3.8 %).
  • Overall, the side effects are considered significant for patients but, particularly given the severity of the disease, are predominantly classified as manageable and treatable. However, no valid conclusions can be drawn regarding the extent of the additional benefit in relation to adverse events on the basis of the available data, particularly given the limited safety data and the limitations of the study described.

Courtesy translation only, please refer to the German original.