Brexucabtagen-Autoleucel / Autologe Anti-CD19-transduzierte CD3+ Zellen (2) – Tecartus®, Autologe Anti-CD19-transduzierte CD3-positive Zellen

• Clinical trials
  • The ZUMA-3 study is a single-arm Phase I/II trial investigating the efficacy and safety of brexucabtagen-autoleucel in adults with relapsed or refractory B-cell precursor ALL.
  • For an indirect comparison of efficacy, the pharmaceutical manufacturer presents the SCHOLAR-3 study, which is based on historical data from clinical trials.

Adults aged 26 years and over with relapsed or refractory B-cell precursor <ul><li>acute lymphoblastic leukaemia (ALL)</li></ul>

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• The certainty of the findings is assessed as a hint, as a comparative assessment is not possible on the basis of the single-arm, uncontrolled ZUMA-3 trial, and no comparative data suitable for benefit assessment have been provided.
• mortality
  • Overall survival was defined in the ZUMA-3 study as the time from study enrolment to death from any cause.
  • At the time of the data cut-off (median follow-up duration: 25.1 months), 50.6% of patients had died with regard to the FAS.
  • The Kaplan-Meier estimate at month 24 was 48.2 per cent and the median overall survival was 23.1 months.
  • Due to the single-arm study design, a comparative assessment of the overall survival data is not possible.
• Morbidity – Complete Overall Remission (OCR)
  • The endpoint ‘complete overall remission’ (OCR) was the primary endpoint of the ZUMA-3 study and included patients who achieved CR, CRi or an allogeneic haematopoietic stem cell transplant.
  • With regard to the FAS, 53.4% (central review) and 58.0% (review by the medical trial staff) of the Phase II cohort in the ZUMA-3 study achieved OCR.
  • Due to the single-arm study design, a comparative assessment of OCR is not possible.
• Morbidity – Minimal residual disease (MRD negativity)
  • The presence of minimal residual disease (MRD) was assessed in the ZUMA-3 study using quantitative PCR (qPCR) or flow cytometry and was defined as < 10⁻⁴ leukaemic blasts in the bone marrow.
  • According to central review, 59% of patients in the Phase II cohort of the ZUMA-3 study had achieved MRD negativity at the time of the data cut-off.
  • Achieving MRD negativity is regarded as an important prognostic factor in the treatment of ALL.
  • There is no validation of MRD negativity as a surrogate marker for overall survival. The endpoint of MRD negativity is classified as an endpoint of unclear relevance and is presented as supplementary information.
  • Irrespective of this, a comparative assessment of MRD negativity is not possible due to the single-arm study design.
• Morbidity – Duration of response
  • In the ZUMA-3 study, duration of response was defined as the time from the first CR or CRi until relapse or death from any cause.
  • A total of 47 patients in the Phase II cohort of the ZUMA-3 study achieved a CR or CRi. At the time of the data cut-off, 40% of these patients had relapsed; 3 (6%) patients had died. The median event-free survival was 13.7 months.
  • Due to the single-arm study design, a comparative assessment of the duration of response is not possible.
• quality of life
  • No data on health-related quality of life were collected in the ZUMA-3 study.
• Side effects
  • In the ZUMA-3 study, all patients who received a brexucabtagen-autoleucel infusion (Safety Analysis Set (SAS)) experienced an adverse event.
  • Based on the SAS, 78% of patients experienced a serious adverse event (SAE). The most commonly observed events were vascular disorders, nervous system disorders, and infections and infestations.
  • Severe adverse events (CTCAE ≥ Grade 3) occurred in a total of 97% of patients. Particularly common were disorders of the blood and lymphatic system, abnormal laboratory parameters (MedDRA system organ class ‘Investigations’), general disorders and administration site conditions, and metabolic and nutritional disorders.
  • Relevant adverse events of particular interest included cytopenia, neurological events, cytokine release syndrome and infections.
  • Due to the single-arm study design, a comparative assessment of the endpoints within the ‘side effects’ endpoint category is not possible.
• Overall assessment / Conclusion
  • Results from the ZUMA-3 study are available for the benefit assessment of brexucabtagen-autoleucel in the treatment of adults aged 26 years and over with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia, results from the ZUMA-3 study are available for the endpoint categories of mortality, morbidity and adverse events.
  • Due to the single-arm design of the ZUMA-3 study, a comparative assessment is not possible.
  • The indirect comparison submitted by the pharmaceutical manufacturer is not acceptable due to the lack of transparency regarding the methodology used to identify potential confounders, the uncertainties regarding the positivity of the patient populations used for the indirect comparison, and the division of the historical control cohort into the synthetic control arms, the uncertainties regarding adherence to the pre-specified methodology for the propensity score procedure, and the unclear representativeness of the patient population included in the analysis for the patients covered by the therapeutic indication, is subject to major uncertainty.
  • Furthermore, due to the highly selected patient population in the indirect comparison and the unclear representativeness for patients in the therapeutic indication, the resulting effect estimates cannot be meaningfully interpreted. The indirect comparison presented between the ZUMA-3 study and the SCHOLAR-3 study is therefore not suitable for the present benefit assessment.
  • Consequently, the G-BA classifies the extent of the additional benefit of brexucabtagen-autoleucel in the present indication as non-quantifiable, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.