Ibrutinib (9) – Imbruvica®

• Clinical trials
  • The GLOW trial is an open-label, multicentre, randomised, controlled Phase III trial, which has been ongoing since April 2018, in which ibrutinib + venetoclax was compared with chlorambucil + obinutuzumab.

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

• The additional benefit is not proven.
• Overall, for ibrutinib in combination with venetoclax in adult patients with previously untreated chronic lymphocytic leukaemia (CLL) without genetic risk factors, who, based on their general health and comorbidities, are not suitable for treatment with FCR, no additional benefit has been established compared with chlorambucil in combination with obinutuzumab.
• mortality
  • For the endpoint of overall survival, there is no statistically significant difference between ibrutinib in combination with venetoclax and chlorambucil in combination with obinutuzumab.
• Morbidity – Progression-free survival
  • PFS is statistically significantly prolonged with ibrutinib in combination with venetoclax compared with chlorambucil in combination with obinutuzumab.
  • The available data from the GLOW study do not indicate that the prolonged PFS observed with ibrutinib in combination with venetoclax is associated with an improvement in morbidity (symptoms, health status) or quality of life. The results for the PFS endpoint are therefore not taken into account in this assessment.
• Morbidity – Symptoms
  • Symptoms were assessed in the GLOW study using the symptom scales of the EORTC QLQ-C30 and the FACIT-Fatigue.
  • For the endpoint of diarrhoea, assessed using the EORTC QLQ-C30, there is a disadvantage for ibrutinib in combination with venetoclax.
  • For the other endpoints, there was no statistically significant difference between the treatment groups.
  • Overall, no positive or negative effects of ibrutinib in combination with venetoclax were observed with regard to symptoms.
• Morbidity – Health status
  • Health status is assessed in the GLOW study using the visual analogue scale (VAS) of the EQ-5D.
  • For the health status endpoint, there is no statistically significant difference between the treatment arms.
  • When the results for symptoms and health status are considered together, no difference relevant to the benefit assessment was found between the treatment groups.
• Health-related quality of life
  • Quality of life among patients in the GLOW study is assessed using the functional scales of the EORTC QLQ-C30 questionnaire.
  • No statistically significant difference between the treatment groups was observed for any of the health-related quality of life scales.
  • When the results are considered as a whole, there are neither positive nor negative effects of ibrutinib in combination with venetoclax on health-related quality of life.
• Side effects – Total adverse events
  • Adverse events occurred in all participants in the GLOW trial. The results for the endpoint ‘Total adverse events’ are presented here for supplementary information only.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuation due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuation due to AEs.
• Side effects – Specific AEs
  • For the endpoints haemorrhages (AE), haemorrhages (severe AEs), cardiac disorders (severe AEs), and infections and parasitic diseases (severe AEs), no statistically significant difference was observed between the treatment groups in each case.
  • For the endpoint ‘infusion-related reaction’, the analysis submitted by the pharmaceutical manufacturer is not suitable for assessing additional benefit; however, serious and severe infusion reactions are taken into account in the overall rates of SAE and severe AEs.
  • In the overall assessment of the results regarding side effects, there is neither an advantage nor a disadvantage for ibrutinib in combination with venetoclax.
• Overall assessment
  • For the assessment of the additional benefit of ibrutinib in combination with venetoclax, results from the GLOW study are available comparing it with chlorambucil in combination with obinutuzumab across the endpoint categories of mortality, morbidity, quality of life and side effects.
  • For the endpoint of overall survival, there is no statistically significant difference between ibrutinib in combination with venetoclax and chlorambucil in combination with obinutuzumab.
  • With regard to symptoms (assessed using the EORTC QLQ-C30 and FACIT-Fatigue) and health status (assessed using the EQ5D-VAS), no difference relevant to the benefit assessment was found overall between the treatment groups.
  • With regard to the health-related quality of life endpoint category (assessed using the EORTC QLQ-C30), there were neither positive nor negative effects for ibrutinib in combination with venetoclax.
  • For the endpoint category of side effects, there is neither an advantage nor a disadvantage associated with ibrutinib in combination with venetoclax.
  • Given the minor number of patients in the relevant patient population, the precision of the results for the endpoints is generally low.

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) without genetic risk factors, who, based on their general condition and comorbidities, are suitable for treatment with FCR, and for adults with genetic risk factors, the pharmaceutical manufacturer has not provided any data for the assessment of additional benefit. Consequently, an additional benefit is not proven.

Courtesy translation only, please refer to the German original.