Zanubrutinib (4) – Brukinsa®

a) Adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) who have not received either a BTK inhibitor or a BCL2 inhibitor

• The overall assessment provides an indication of a minor additional benefit compared with ibrutinib.
• mortality
  • The endpoint of overall survival was defined in the ALPINE trial as the time from the start of trial treatment to death from any cause. No statistically significant difference was observed between the treatment arms.
  • With regard to overall survival, therefore, the additional benefit of zanubrutinib compared with ibrutinib is not proven.
  • For this endpoint, there is an effect modification by the characteristic of age. A statistically significant advantage in favour of zanubrutinib was observed for patients aged < 65 years. In contrast, for patients aged ≥ 65 years, no statistically significant difference was observed between the treatment arms.
  • This effect modification is not observed for other endpoints. Overall, the validity of the available subgroup results is considered insufficient for the assessment of additional benefit.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS) is defined in the study as the time from the start of study treatment to the first documented disease progression or to death, whichever occurred first. For PFS, there is a statistically significant advantage in favour of zanubrutinib compared with ibrutinib.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • For the endpoints of fatigue, nausea and vomiting, pain, loss of appetite, dyspnoea, insomnia and constipation, there is no statistically significant difference between the treatment arms in each case.
  • Only for the endpoint of diarrhoea was there a statistically significant difference between the treatment arms in favour of zanubrutinib.
• Morbidity – Health status (EQ-5D VAS)
  • For the health status endpoint, assessed using the EQ-5D VAS, there was no statistically significant difference between the treatment arms.
• Health-related quality of life
  • For the endpoints of general health status, physical function, role functioning, cognitive functioning, emotional functioning and social functioning, there was no statistically significant difference between the treatment arms in any case.
  • There was no statistically significant difference between the treatment arms with regard to health-related quality of life.
• Side effects – serious AEs (SAEs) and discontinuation due to AEs
  • For the endpoints of SAEs and discontinuation due to AEs, a statistically significant advantage was observed in favour of zanubrutinib compared with ibrutinib.
• Side effects – severe AEs
  • For the endpoint ‘severe AEs’, there was no statistically significant difference between the treatment arms.
• Side effects – cardiac events (severe AEs)
  • For the endpoint of cardiac events (severe AEs), there was a statistically significant advantage for zanubrutinib compared with ibrutinib.
• Side effects – muscle spasms (AE)
  • For the endpoint of muscle spasms (AE), there was a statistically significant advantage for zanubrutinib compared with ibrutinib.
• Side effects – infections and parasitic diseases (severe AEs) and haemorrhages (AEs)
  • For the endpoints infections and parasitic diseases (severe AEs) and bleeding (AEs), no statistically significant difference was observed between the treatment arms in either case.
• Overall assessment / Conclusion
  • This benefit assessment of zanubrutinib as monotherapy for the treatment of adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) who have not received either a BTK inhibitor or a BCL2 inhibitor is based on the results of the ALPINE study regarding the endpoint categories of mortality, morbidity, health-related quality of life and side effects, compared with ibrutinib.
  • For the endpoint of overall survival, there was no statistically significant difference between the treatment arms.
  • For the endpoint categories of morbidity, as assessed using the symptom scales of the EORTC QLQ-C30 questionnaire and the EQ-5D VAS, and for the endpoint category of health-related quality of life, as assessed using the functional scales of the EORTC QLQ-C30 questionnaire, no relevant advantages or disadvantages were observed.
  • With regard to side effects, there are positive effects of zanubrutinib compared with ibrutinib for the endpoints of SAEs, treatment discontinuation due to AEs, and, in detail, for specific AEs. The extent of the advantage is assessed as minor overall.
  • In the overall assessment, therefore, a small net benefit was identified for zanubrutinib as monotherapy for the treatment of adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) who have not received either a BTK inhibitor or a BCL2 inhibitor is assessed as having a minor additional benefit compared with ibrutinib.

b) Adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) following prior treatment with at least one BTK inhibitor

• An additional benefit is not proven.
• For adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) following prior treatment with at least one BTK inhibitor, the pharmaceutical manufacturer has not provided any data for the assessment of additional benefit. Consequently, additional benefit is not proven.

c) Adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) following prior treatment with at least one BCL2 inhibitor

• An additional benefit is not proven.
• For adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) following prior treatment with at least one BCL2 inhibitor, the pharmaceutical manufacturer has submitted the ALPINE study. Few patients with relapsed/refractory CLL, following prior treatment with at least one BCL2 inhibitor, were included in the study (zanubrutinib N = 7, ibrutinib N = 8). The pharmaceutical manufacturer has not provided separate analyses for this small patient population. The ALPINE study is not relevant for benefit assessment for patients with relapsed/refractory CLL following prior treatment with at least one BCL2 inhibitor.
• Consequently, there are no suitable data available to assess the additional benefit of zanubrutinib compared with the appropriate comparator therapy. Therefore, the additional benefit is not proven.

d) Adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) following prior treatment with at least one BTK inhibitor and one BCL2 inhibitor

• An additional benefit is not proven.
• For adults with relapsed/refractory chronic lymphocytic leukaemia (CLL) following prior treatment with at least one BTK inhibitor and one BCL2 inhibitor, the pharmaceutical manufacturer has not provided any data for the assessment of additional benefit. Consequently, the additional benefit is not proven.

Courtesy translation only, please refer to the German original.