Acalabrutinib (3) – Calquence®

• Clinical trials
  • This benefit assessment of acalabrutinib is based on the results of the pivotal, randomised, open-label, Phase III ASCEND trial, in which acalabrutinib was compared with bendamustine + rituximab or idelalisib + rituximab, depending on the investigator’s choice.

a2) Adult patients with chronic lymphocytic leukaemia who have received prior treatment, who do not have a 17p deletion or TP53 mutation, and for whom chemo-immunotherapy is indicated, and for whom a therapy other than bendamustine in combination with rituximab represents the appropriate treatment for the individual patient

• The additional benefit is not proven.
• For the patient population of patients with chronic lymphocytic leukaemia following prior treatment who do not have a 17pdeletion or TP53 mutation, for whom chemo-immunotherapy is indicated, and for whom a treatment other than bendamustine in combination with rituximab constitutes the individually appropriate therapy, no conclusions regarding additional benefit can be drawn, taking into account the ASCEND study. As only results comparing the treatment with bendamustine in combination with rituximab were submitted for the benefit assessment, no usable data are available overall.

b) Adult patients with chronic lymphocytic leukaemia following prior treatment who have a 17p deletion or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons

• mortality
  • In the ASCEND 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 (PFS) was the primary endpoint in the ASCEND trial 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 demonstrated a statistically significantly longer progression-free survival than the comparator arm receiving idelalisib + rituximab.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • For the present assessment, the responder analyses are defined as the time to the first deterioration of ≥ 15 % of the scale range compared with baseline. There is no statistically significant difference between the treatment groups.
  • For the present assessment, the responder analyses are operationalised as the time to the first deterioration of ≥ 15 points compared with baseline. No statistically significant differences were observed between the treatment groups.
  • For the present analysis, the responder analyses are operationalised as the time to the first deterioration of ≥ 15 points compared with baseline. No statistically significant difference was observed between the treatment groups.
• Health-related quality of life – EORTC QLQ-C30 (functional scales)
  • Health-related quality of life is assessed in the ASCEND study using the functional scales of the EORTC QLQ-C30 until disease progression.
  • For the present evaluation, the responder analyses are operationalised as the time to the first deterioration of ≥ 15 points compared with baseline. No statistically significant differences were observed between the treatment groups.
• Side effects
  • Endpoints in the side effect category were recorded up to 30 days after the end of treatment.
  • With regard to SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs (≥ 1 component), there is a statistically significant advantage in each case for acalabrutinib compared with idelalisib + rituximab.
  • In detail, when examining the specific adverse events for the endpoints ‘Infections and parasitic diseases’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘General disorders and administration site conditions’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Respiratory, thoracic and mediastinal disorders’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Skin and subcutaneous tissue disorders’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Renal failure’ (PT, severe AE [CTCAE grade ≥ 3]), ‘Blood and lymphatic system disorders’ (SOC, severe AEs [CTCAE grade ≥ 3]), ‘Gastrointestinal disorders’ (SOC, severe AEs [CTCAE grade ≥ 3]), ‘Hepatic and biliary disorders’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Metabolic and nutritional disorders’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Investigations’ (SOC, severe AEs [CTCAE grade ≥ 3])”, a statistically significant advantage in favour of acalabrutinib compared with idelalisib + rituximab was observed in each case.
  • For the endpoint “headache” (PT, AE), a statistically significant difference was observed to the disadvantage of acalabrutinib compared with idelalisib + rituximab.
  • An overall review of the endpoints relating to side effects reveals advantages for acalabrutinib compared with idelalisib + rituximab in terms of serious adverse events, severe adverse events (CTCAE grade ≥ 3), therapy discontinuations due to adverse events (≥ 1 component) and, in detail, predominantly for specific adverse events. Overall, the extent of the differences is substantial and represents a significant improvement in therapeutic benefit compared with idelalisib + rituximab.
• Overall assessment
  • For the assessment of the additional benefit of acalabrutinib in the treatment of adult patients with chronic lymphocytic leukaemia (CLL) following prior therapy, who have a 17p deletion or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons, results are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • There is no statistically significant difference in overall survival between the treatment groups.
  • For the endpoints in the morbidity category, assessed using the FACIT-Fatigue, EORTC-QLQ-C30 and the visual analogue scale of the EQ-5D, there was no statistically significant difference between the treatment groups in any case.
  • The data on health-related quality of life, collected using the EORTC-QLQ-C30, also show no statistically significant difference between the treatment groups.
  • In the category of side effects, acalabrutinib showed advantages in terms of serious adverse events, severe adverse events (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events. In detail, an analysis of specific adverse events also shows predominantly advantages for treatment with acalabrutinib. Given the significant extent of the positive effects observed, there is an overall clear advantage for acalabrutinib compared with idelalisib + rituximab in the ‘side effects’ endpoint category.
  • In the overall assessment of the results for patient-relevant endpoints, there is therefore an advantage for acalabrutinib in the ‘side effects’ category. The extent of the differences in this regard is substantial and represents a significant improvement in therapeutic benefit compared with idelalisib + rituximab.
  • Consequently, for acalabrutinib in the treatment of adult patients with chronic lymphocytic leukaemia (CLL) following prior therapy, who have a 17p deletion or TP53 mutation, or for whom chemo-immunotherapy is not indicated for other reasons, a considerable additional benefit has been established.

c1) Adult patients with chronic lymphocytic leukaemia who have received at least two prior treatments, for whom idelalisib in combination with rituximab or rituximab in combination with bendamustine represents the appropriate treatment on a case-by-case basis

• Hint for a minor additional benefit
• mortality
  • In the ASCEND trial, the endpoint of overall survival is defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the two treatment groups.
• morbidity
  • Progression-free survival (PFS) was the primary endpoint in the ASCEND 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 demonstrated a statistically significantly longer progression-free survival than the comparator arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • For the present evaluation, the responder analyses are operationalised as the time to the first deterioration of ≥ 15 % of the scale range compared with baseline. There is no statistically significant difference between the treatment groups.
  • For the symptom scales fatigue, pain and insomnia, a statistically significant difference was observed in each case to the disadvantage of acalabrutinib compared with bendamustine + rituximab and idelalisib + rituximab, respectively. For the nausea and vomiting symptom scale, there is a statistically significant advantage of acalabrutinib compared with bendamustine + rituximab and idelalisib + rituximab, respectively.
  • For the present assessment, the responder analyses are operationalised as time to the first deterioration of ≥ 15 points compared with baseline. No statistically significant difference was observed between the treatment groups.
• Health-related quality of life – EORTC QLQ-C30 (functional scales)
  • Health-related quality of life is assessed in the ASCEND study using the functional scales of the EORTC QLQ-C30 until disease progression.
  • For the physical functioning subscale, a statistically significant difference was observed in favor of bendamustine + rituximab compared with acalabrutinib and idelalisib + rituximab.
• Side effects
  • Endpoints in the side effect category were recorded up to 30 days after the end of treatment.
  • With regard to SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs (≥ 1 component), there is a statistically significant advantage in each case for acalabrutinib compared with bendamustine + rituximab and idelalisib + rituximab, respectively.
  • In detail, when examining the specific adverse events for the endpoints ‘Infections and parasitic diseases’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Blood and lymphatic system disorders’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Gastrointestinal disorders’ (SOC, severe AE [CTCAE grade ≥ 3]), ‘Investigations’ (SOC, severe AEs [CTCAE grade ≥ 3])”, a statistically significant advantage for acalabrutinib compared with bendamustine + rituximab or idelalisib + rituximab.
  • For the endpoint “headache” (PT, AEs), there was a statistically significant difference in favor of bendamustine + rituximab compared with acalabrutinib and idelalisib + rituximab, respectively.
  • In the overall analysis of the adverse event endpoints, acalabrutinib showed advantages over bendamustine + rituximab and idelalisib + rituximab, respectively, in terms of serious adverse events, severe adverse events (CTCAE grade ≥ 3), therapy discontinuations due to adverse events (≥ 1 component) and, in detail, for specific adverse events. Overall, the extent of the differences is substantial and represents a significant improvement in therapeutic benefit compared with bendamustine + rituximab and idelalisib + rituximab, respectively.
• Overall assessment
  • Results are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects to assess the additional benefit of acalabrutinib for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least two prior treatments.
  • No statistically significant difference in overall survival was observed between the treatment groups.
  • For the endpoints in the morbidity category, analyses are available on symptoms using the FACIT-Fatigue and EORTC-QLQ-C30 assessment tools, and on health status using the EQ-5D visual analogue scale. Overall, statistically significant disadvantages of acalabrutinib compared with bendamustine + rituximab or idelalisib + rituximab were observed on the symptom scales for fatigue, pain and insomnia. In contrast, a statistically significant advantage of acalabrutinib was observed compared with bendamustine + rituximab and idelalisib + rituximab, respectively, on the nausea and vomiting symptom scale.
  • For the endpoints in the health-related quality of life category, assessed using the EORTC-QLQ-C30 questionnaire, acalabrutinib showed a statistically significant disadvantage compared with bendamustine + rituximab and idelalisib + rituximab on the physical functioning subscale.
  • In the ‘side effects’ category, acalabrutinib showed advantages in terms of serious adverse events, severe adverse events (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events. In detail, an analysis of specific adverse events also reveals advantages for treatment with acalabrutinib. Given the considerable extent of these positive effects, there is an overall clear advantage for acalabrutinib in the ‘side effects’ endpoint category.
  • In the overall assessment of the results for patient-relevant endpoints, moderate disadvantages for acalabrutinib can be identified in the category of morbidity and health-related quality of life. These are offset by advantages in the ‘side effects’ category, which have a substantial extent and represent a significant improvement in therapeutic benefit compared with bendamustine + rituximab or idelalisib + rituximab.
  • Consequently, the G-BA concludes that acalabrutinib offers a minor additional benefit for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least two prior treatments.

c2) Adult patients with chronic lymphocytic leukaemia who have received at least two prior treatments, for whom a therapy other than idelalisib in combination with rituximab or rituximab in combination with bendamustine represents the appropriate treatment on a case-by-case basis

• An additional benefit is not proven.
• For the patient population of patients with chronic lymphocytic leukaemia who have received at least two prior treatments and for whom a therapy other than idelalisib in combination with rituximab or rituximab in combination with bendamustine represents the appropriate treatment on an individual basis, no conclusions regarding additional benefit can be drawn on the basis of the ASCEND study. As the benefit assessment was based exclusively on results comparing these treatments with idelalisib in combination with rituximab and rituximab in combination with bendamustine, no usable data are available overall.

Courtesy translation only, please refer to the German original.