Acalabrutinib (5) – Calquence®

• Clinical trials
  • The ongoing ECHO trial is a double-blind, randomised, controlled trial comparing acalabrutinib in combination with BR against placebo in combination with BR in adults with previously untreated mantle cell lymphoma.

a1) Adults with untreated mantle cell lymphoma who are not suitable for autologous stem cell transplantation and for whom bendamustine in combination with rituximab constitutes a suitable individualised treatment

• The additional benefit is not proven.
• mortality
  • In the ECHO study, overall survival was defined as the time from randomisation to death from any cause, regardless of whether patients discontinued the randomised treatment or received follow-up therapy.
  • No statistically significant difference in overall survival was observed between the treatment arms.
  • In the G-BA’s view, the unequal use of follow-up therapies between the study arms results in an increased potential for endpoint-specific bias.
• Morbidity – Progression-free survival (PFS)
  • PFS is the primary endpoint of the ECHO study and is defined as the time from randomisation to disease progression or death from any cause, whichever occurs first.
  • There is a statistically significant difference in favour of acalabrutinib + BR compared with BR.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
• Morbidity – EORTC QLQ-C30 symptom scales
  • In the ECHO study, disease symptoms are assessed using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire. In the dossier, the pharmaceutical manufacturer presents responder analyses for the time to first deterioration of ≥ 10 points.
  • For the pain and diarrhoea symptom scales, there is a statistically significant difference to the detriment of acalabrutinib + BR compared with BR.
  • For the remaining symptom scales, there are no statistically significant differences between the treatment arms.
  • Overall, there is a disadvantage in terms of symptoms, which is considered relevant in terms of clinical significance but no more than minor in terms of its extent.
• Morbidity – Health status (EQ-5D VAS)
  • Health status is assessed in the ECHO study using the visual analogue scale (VAS) of the European Quality of Life Questionnaire 5 Dimensions (EQ-5D) and is presented in the dossier as a responder analysis for the time to first deterioration by ≥ 15 points.
  • There is no statistically significant difference in health status between the study arms.
• Health-related quality of life – EORTC QLQ-C30 functional scales
  • Health-related quality of life is assessed in the ECHO study using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire. The pharmaceutical manufacturer presents responder analyses in the dossier for the time to first deterioration of ≥ 10 points.
  • For the individual health-related quality of life scales of the EORTC QLQ-C30, there is no statistically significant difference between the study arms.
• Side effects – serious AEs (SAEs) and severe AEs
  • In the ECHO study, no statistically significant differences between the study arms were observed for the endpoints SAE and severe AEs.
• Conclusion on side effects
  • Overall, there are no statistically significant differences between the treatment arms in the side effect endpoint category for SAE and severe AEs. For the endpoint ‘therapy discontinuations due to AEs’, there is a disadvantage for the acalabrutinib combination. In detail, for specific AEs, there are predominantly disadvantages for the acalabrutinib combination.
  • Overall, a disadvantage in the ‘side effects’ endpoint category is inferred on the basis of the disadvantage regarding ‘therapy discontinuations due to side effects’.
• Overall assessment
  • For the assessment of the additional benefit of acalabrutinib in combination with bendamustine and rituximab (BR) for the treatment of adults with untreated mantle cell lymphoma who are not suitable for autologous stem cell transplantation and for whom BR represents a suitable individualised therapy, results are available for the endpoint categories of mortality, morbidity, quality of life and side effects from the ECHO study, which compared acalabrutinib + BR with BR.
  • No statistically significant difference in overall survival was observed between the study arms. The overall survival results are subject to uncertainty, as there were differences in the use of follow-up therapies between the study arms.
  • With regard to morbidity, a minor disadvantage can be observed for pain and diarrhoea based on the symptom scales of the EORTC QLQ-C30. No difference relevant to the benefit assessment was observed in the remaining symptom scales of the EORTC QLQ-C30 or for the health status endpoint (EQ-5D VAS). Due to the disadvantage regarding pain and diarrhoea in the EORTC QLQ-C30 symptom scales, an overall disadvantage is inferred in the morbidity endpoint category.
  • With regard to health-related quality of life, neither an advantage nor a disadvantage can be inferred from the patient-reported endpoints (functional scales of the EORTC QLQ-C30, FACT-Lym).
  • With regard to the ‘side effects’ endpoint category, there are no statistically significant differences between the treatment arms in the overall rates of severe SAEs and severe AEs. For ‘therapy discontinuations due to AEs’, the acalabrutinib combination shows a disadvantage. For individual specific side effects, the acalabrutinib combination therapy predominantly showed disadvantages. Due to the disadvantage in ‘therapy discontinuations due to side effects’, an overall disadvantage is inferred in the ‘side effects’ endpoint category.
  • Overall, there are no positive effects observed for patient-relevant endpoints. The endpoints ‘pain’ and ‘diarrhoea’ (EORTC QLQ-C30) show adverse effects for acalabrutinib in combination with BR; furthermore, a disadvantage is observed in terms of side effects due to the increase in ‘therapy discontinuations due to AEs’. Taking into account the minor extent of the adverse effects on symptoms, the uncertainties regarding overall survival and the limited certainty of the results concerning the increase in therapy discontinuations due to adverse events, the G-BA concludes, following a weight-of-evidence assessment, that an additional benefit is not proven for acalabrutinib in combination with BR for the treatment of adults with untreated mantle cell lymphoma who are not suitable for autologous haematopoietic stem cell transplantation and for whom BR represents a suitable individualised therapy.

a2) Adults with untreated mantle cell lymphoma who are not suitable for autologous stem cell transplantation and for whom bendamustine in combination with rituximab does not constitute a suitable individualised therapy

• The additional benefit is not proven.
• The ECHO study is not suitable for determining additional benefit, as only the BR combination was used in the comparator arm of this study. Consequently, additional benefit is not proven for adults for whom BR does not constitute a suitable individualised therapy.

Courtesy translation only, please refer to the German original.