Zanubrutinib (2) – Brukinsa®

• Clinical trials
  • The benefit assessment is based on the results of the randomised, open-label, ongoing Phase III SEQUOIA trial. The trial compares zanubrutinib with bendamustine in combination with rituximab (BR).

a) Adults with previously untreated chronic lymphocytic leukaemia (CLL) without genetic risk factors, who, based on their general condition and comorbidities, are not suitable for treatment with FCR

• Overall, a minor additional benefit is identified for zanubrutinib.
• Overall, a hint for confidence in the established additional benefit is derived.
• mortality
  • For the endpoint of overall survival, no statistically significant difference was observed between zanubrutinib and BR.
  • No advantage or disadvantage of zanubrutinib over BR can therefore be identified with regard to overall survival.
• Morbidity – Progression-free survival
  • PFS is statistically significantly prolonged with zanubrutinib compared with BR.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of morbidity is not assessed on the basis of symptoms, but predominantly by means of laboratory parameters, imaging and haematological procedures. 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 additional benefit.
• Morbidity – Symptoms
  • Symptoms were assessed in the SEQUOIA study using the symptom scales of the EORTC QLQ-C30 questionnaire.
  • No statistically significant difference was observed between zanubrutinib and BR for any of the endpoints assessed in the questionnaire relating to symptoms.
• Morbidity – Health status
  • Health status was assessed in the SEQUOIA study using the visual analogue scale (VAS) of the EQ-5D. No statistically significant difference was observed between zanubrutinib and BR for the health status endpoint.
• Health-related quality of life
  • For the endpoints of general health status, physical functioning, cognitive functioning, emotional functioning and social functioning, no statistically significant difference was observed between the treatment arms in any case.
  • Only for the role functioning endpoint there was a statistically significant difference between the treatment arms in favour of zanubrutinib.
  • In the overall assessment of the results, no advantage or disadvantage for zanubrutinib was identified with regard to health-related quality of life.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, no statistically significant difference was observed between the treatment groups.
• Side effects – Severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe AEs (CTCAE grade ≥ 3), a statistically significant advantage was observed in favour of zanubrutinib compared with BR.
• Side effects – Discontinuation due to adverse events
  • For the endpoint of discontinuation due to adverse events, the results from the dossier are used, as this endpoint, given the current data available, only includes events that occurred during the course of treatment with the study medication.
  • There is a statistically significant advantage for zanubrutinib compared with BR.
• Side effects – Specific adverse events
  • For the endpoints of fever (SUEs), blood and lymphatic system disorders (severe AEs) and laboratory tests (severe AEs), as well as nausea (AEs) and hypotension (AEs), a statistically significant advantage was observed between the treatment groups in favour of zanubrutinib.
  • For the endpoints of bleeding (AEs) and contusion (AEs), a statistically significant difference was observed between the treatment arms, with a disadvantage for zanubrutinib.
  • For the endpoints of haemorrhages (severe AEs), cardiac disorders (severe AEs) and infections and parasitic diseases (severe AEs), no statistically significant difference was observed between the treatment arms.
  • No suitable data are available for the endpoint ‘infusion-related reactions’, as, due to the open-label study design (without a placebo infusion) and the routine intravenous administration exclusively in the control arm compared with oral administration in the intervention arm, no comparative data were collected for this endpoint.
• Overall assessment / Conclusion
  • For the endpoint of overall survival, there are no advantages or disadvantages for zanubrutinib.
  • For the endpoint categories of morbidity and health-related quality of life, there are also no advantages or disadvantages for zanubrutinib compared with BR.
  • In the overall assessment of side effects, there are advantages of zanubrutinib over BR in the overall categories of severe AEs (CTCAE ≥ 3) and discontinuation due to AEs, as well as predominantly in the detailed analysis of specific AEs. Overall, this is considered a relevant improvement in terms of side effects.
  • In summary, there is a relevant improvement in terms of side effects. With regard to patient-relevant endpoints concerning overall survival, morbidity and health-related quality of life, no relevant differences are apparent.
  • In its overall assessment, the G-BA concludes that zanubrutinib offers a minor additional benefit compared with BR.

b) Adults with previously untreated chronic lymphocytic leukaemia (CLL) without genetic risk factors who, based on their general condition and comorbidities, are suitable for treatment with FCR, and adults with previously untreated chronic lymphocytic leukaemia (CLL) with genetic risk factors

• An additional benefit is not proven.
• For adults with previously untreated chronic lymphocytic leukaemia (CLL) with genetic risk factors and adults with previously untreated chronic lymphocytic leukaemia (CLL) without genetic risk factors, who, based on their general condition and comorbidities, are suitable for treatment with FCR, the pharmaceutical manufacturer has not provided any data for the assessment of additional benefit. Consequently, the additional benefit is not proven compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.