Pirtobrutinib (2) – Jaypirca®

• Clinical trials
  • In the ongoing BRUIN CLL-321 trial, pirtobrutinib is being compared with an individualised treatment regimen involving the selection of either idelalisib in combination with rituximab or bendamustine in combination with rituximab.

a) Adults with relapsed or refractory chronic lymphocytic leukaemia (CLL) who have previously been treated with a Bruton’s tyrosine kinase inhibitor (BTKi) but not with a B-cell lymphoma-2 (BCL-2) inhibitor

• The additional benefit is not proven.
• The pharmaceutical manufacturer has not provided suitable data for the benefit assessment of this patient population. Therefore, additional benefit is not proven.

b1) Adults with relapsed or refractory chronic lymphocytic leukaemia (CLL) who have previously been treated with a Bruton’s tyrosine kinase inhibitor (BTKi) and with a B-cell lymphoma-2 (BCL-2) inhibitor and for whom idelalisib + rituximab or bendamustine + rituximab represents the appropriate individualised therapy

• mortality
  • overall survival
  • The endpoint of overall survival was defined in the BRUIN CLL-321 trial as the time from randomisation to death from any cause. No statistically significant difference was observed between the treatment arms.
• morbidity
  • Progression-free survival (PFS)
  • In the BRUIN CLL-321 study, progression-free survival is defined as the time from randomisation to the occurrence of documented disease progression according to the 2018 iwCLL criteria, or death from any cause in the absence of documented disease progression.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of this endpoint is already recorded as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of morbidity is assessed according to the iwCLL 2018 criteria and is therefore not symptom-based, but is determined exclusively 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 assessment of the extent of the additional benefit.
  • EORTC-QLQ C30 and health status according to EQ-5D VAS
  • In the BRUIN CLL-321 study, disease symptoms were assessed using the cancer-specific EORTC-QLQ C30 questionnaire. Health status was assessed in this study using the visual analogue scale (VAS) of the EQ-ED. The data are unsuitable, as the response rates for all questionnaires—particularly in the control arm—declined sharply at an early stage and varied significantly between the study arms. Furthermore, as only a few events occurred at the early assessment time points, this means that the PRO results are, on the whole, not interpretable.
• quality of life
  • EORTC-QLQ C30
  • Health-related quality of life is assessed in the BRUIN CLL-321 study using the functional scales of the EORTC-QLQ C30. The data are unsuitable, as the response rates for all questionnaires declined sharply at an early stage, particularly in the control arm, and showed significant differences between the study arms. Furthermore, as only a few events had occurred at the early assessment time points, this means that the PRO results cannot be interpreted as a whole.
• Side effects
  • Endpoints in the side effect category were recorded up to 28 days after the end of treatment.
  • Total adverse events (AEs)
  • Almost all study participants experienced an adverse event. These are presented here for supplementary information only.
  • Serious adverse events (SAEs)
  • For the SUE endpoint, there was no statistically significant difference between the treatment arms in the study.
  • Severe AEs
  • For the endpoint of severe AEs, a statistically significant advantage was observed in favour of pirtobrutinib.
  • However, there is an effect modification for the Rai stage. For patients in Rai stages 0–II, pirtobrutinib showed an advantage, whilst for patients in Rai stages III–IV, there was no significant difference. Given that this effect modification is only evident for one endpoint, the result for the overall population is used for the assessment.
  • Discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, the study shows a statistically significant advantage for pirtobrutinib.
  • Specific adverse events:
  • Infections and parasitic diseases (AEs) and cardiac disorders (AEs)
  • For the endpoints of infections and parasitic diseases, as well as cardiovascular diseases, there is no statistically significant difference between the treatment arms in either case.
  • Bleeding (severe AEs, AEs)
  • No suitable data are available for the endpoints of bleeding (severe AEs and AEs).
  • Other specific AEs
  • For the other specific AEs: bronchitis, fever, injury, poisoning and procedure-related complications, renal and urinary tract disorders, diarrhoea, investigations, disorders of the skin and subcutaneous tissue, metabolic and nutritional disorders, liver and biliary disorders, and vascular disorders, the study showed statistically significant advantages in each case for pirtobrutinib.
• Overall assessment
  • For the assessment of the additional benefit of pirtobrutinib in the treatment of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who have previously been treated with a Bruton’s tyrosine kinase inhibitor (BTKi) and with a B-cell lymphoma-2 (BCL-2) inhibitor, the BRUIN CLL-321 study provides results on mortality and side effects compared with individualised therapy involving the selection of idelalisib in combination with rituximab or bendamustine in combination with rituximab.
  • No significant difference in overall survival was observed between the study arms. The results on overall survival are subject to a high potential for bias, as a large proportion of patients (37%) switched from the control arm to treatment with pirtobrutinib (treatment switching). No additional benefit for pirtobrutinib was therefore identified for the endpoint of overall survival.
  • For the endpoint categories of morbidity and health-related quality of life, the analyses of the EORTC QLQ-C30 and EQ-5D VAS, as the response rates for all questionnaires—particularly in the control arm—declined sharply at an early stage and showed significant differences between the study arms. Consequently, no additional benefit is identified for the endpoint categories of morbidity and health-related quality of life.
  • The results regarding side effects for the endpoints of severe AEs, discontinuation due to AEs and specific AEs each show statistically significant advantages for pirtobrutinib compared with individualised therapy involving the selection of idelalisib in combination with rituximab or bendamustine in combination with rituximab.

b2) Adults with relapsed or refractory chronic lymphocytic leukaemia (CLL) who have previously been treated with a Bruton’s tyrosine kinase inhibitor (BTKi) and a B-cell lymphoma-2 (BCL-2) inhibitor and for whom venetoclax plus rituximab constitutes the appropriate personalised therapy

• The additional benefit is not proven.
• For the patient population for whom venetoclax in combination with rituximab represents the appropriate individualised therapy, no conclusions regarding additional benefit can be drawn from the BRUIN CLL-321 trial. In this study, investigators had access only to idelalisib in combination with rituximab and bendamustine in combination with rituximab, but not to venetoclax in combination with rituximab. Consequently, no data are available for assessing the additional benefit in the patient population.

Courtesy translation only, please refer to the German original.