Acalabrutinib (1) – Calquence®

a) Adult patients with previously untreated chronic lymphocytic leukaemia who do not have a 17p deletion or TP53 mutation and for whom treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is an option

• For acalabrutinib in the treatment of adult patients with previously untreated chronic lymphocytic leukaemia who do not have a 17p deletion or TP53 mutation and for whom treatment with fludarabine in combination with cyclophosphamide and rituximab (FCR) is a suitable treatment option, an additional benefit is not proven.
• The pharmaceutical manufacturer did not submit any data that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

b) Adult patients with untreated chronic lymphocytic leukaemia who do not have a 17p deletion or TP53 mutation and for whom treatment with FCR is not an option

• mortality
  • overall survival
  • In the ELEVATE-TN trial, the endpoint of overall survival is defined as the time from randomisation to death from any cause.
  • There was no statistically significant difference between the two treatment groups.
• morbidity
  • Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint in the ELEVATE-TN study and was assessed by an independent review committee (IRC) in accordance with the iwCLL criteria. PFS is defined as the time from randomisation to disease progression or death from any cause.
  • The acalabrutinib arm showed a significantly longer progression-free survival than the comparator arm of chlorambucil + obinutuzumab.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of morbidity is assessed according to IWCL criteria and thus 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.
• Health-related quality of life – EORTC QLQ-C30 (functional scales)
  • Health-related quality of life is assessed in the ELEVATE-TN study using the functional scales of the EORTC QLQ-C30 up to the point of disease progression.
  • There is no significant difference between the treatment groups.
• Side effects
  • Side effects were recorded in both treatment groups up to 30 days after the last dose of the study medication. Due to the differing observation periods in the treatment groups, the median observation period for this endpoint differs significantly between the two treatment groups (33.4 months in the intervention arm versus 6.1 months in the control arm). Consequently, the hazard ratio (HR) reflects only the first 7 months or so.
  • Serious adverse events (SUEs)
  • No statistically significant difference was observed between the treatment groups for the SUE endpoint.
  • Severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe AEs (CTCAE grade ≥ 3), a statistically significant advantage was observed in favour of acalabrutinib compared with chlorambucil + obinutuzumab.
  • Discontinuation due to AEs (≥ 1 component)
  • For the endpoint ‘discontinuation due to AEs (≥ 1 component)’, there was a statistically significant advantage for acalabrutinib compared with chlorambucil + obinutuzumab.
  • Specific AEs
  • In detail, when examining the specific adverse events for the endpoints ‘nausea’ (PT, AE), ‘Blood and lymphatic system disorders’ (SOC, severe AEs), including ‘febrile neutropenia’ (PT, severe AEs), and ‘Metabolic and nutritional disorders’ (SOC, severe AEs), including ‘tumour lysis syndrome’ (PT, severe AEs), there is a statistically significant advantage in each case for acalabrutinib compared with chlorambucil + obinutuzumab.
  • For the endpoints “Infections and parasitic diseases” (SOC, AEs) and “Cardiac disorders” (SOC, AEs), no statistically significant difference was observed between the treatment groups.
  • As no events occurred in the comparator arm in each case, no event-time analyses can be performed for the endpoint ‘bleeding’ (SMQ, severe AEs).
  • An overall review of the side effect endpoints reveals exclusively advantages for acalabrutinib compared with chlorambucil + obinutuzumab. These are evident in severe side effects (CTCAE grade ≥ 3), treatment discontinuation due to side effects, and, in detail, for specific side effects. Due to the short observation period in the comparator arm, the event duration analyses allow comparative conclusions to be drawn only for the first 7 months of treatment. Comparative conclusions regarding side effects occurring in the longer term cannot be drawn on the basis of the data.
• Overall assessment
  • For the assessment of the additional benefit of acalabrutinib in the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL), who do not have a 17p deletion or TP53 mutation and for whom treatment with FCR is not an option, data are available from the ELEVATE-TN trial for a relevant patient population (patients unsuitable for treatment with FCR) regarding mortality, morbidity, health-related quality of life and side effects, compared with chlorambucil in combination with obinutuzumab.
  • There is no statistically significant difference between the two treatment groups for the endpoint of overall survival. An additional benefit in terms of overall survival is therefore not proven.
  • For the morbidity endpoints assessed using the FACIT-Fatigue, EORTC-QLQ-C30 and the EQ-5D visual analogue scale (VAS), a significant advantage in favour of acalabrutinib was observed only for the EQ-5D VAS.
  • The data on health-related quality of life, collected using the EORTC-QLQ-C30, show no significant difference between the treatment groups.
  • In the category of side effects, acalabrutinib showed advantages in terms of severe side effects (CTCAE grade ≥ 3) and treatment discontinuation due to side effects. These advantages were particularly evident in relation to acute side effects. In detail, an analysis of specific adverse events also reveals advantages exclusively in the intervention arm. However, due to the short observation period in the control arm, event-time analyses allow comparative conclusions to be drawn only for the first 7 months of treatment.
  • Overall, therefore, there is an advantage in the morbidity category and in the side effect category.
  • On balance, based on the available data, a small additional benefit can be inferred for acalabrutinib compared with chlorambucil plus obinutuzumab in adult patients with previously untreated chronic lymphocytic leukaemia who do not have a 17p deletion or TP53 mutation and for whom treatment with FCR is not an option. a minor additional benefit can be inferred compared with chlorambucil + obinutuzumab.

c) Adult patients with previously untreated chronic lymphocytic leukaemia who have a 17p deletion or a TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons

• An additional benefit is not proven for acalabrutinib in the treatment of adult patients with previously untreated chronic lymphocytic leukaemia with a 17p deletion or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons.
• The pharmaceutical manufacturer did not submit any data that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.