Blinatumomab (5) – Blincyto®

• Clinical trials
  • The ALCANTARA study is a single-arm, open-label Phase II study.
  • The 20160462 study is a retrospective, non-interventional cohort study based on databases from three study centres in Italy and Spain.
  • In the controlled TOWER trial, blinatumomab was compared with salvage chemotherapy in a population of patients with relapsed or refractory Philadelphia chromosome-negative B-precursor ALL.

Adult patients with Philadelphia chromosome-positive, CD19-positive, relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL), in whom treatment with at least two tyrosine kinase inhibitors (TKIs) has failed and who have no alternative treatment options

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• The certainty of the evidence is assessed as a hint because only a single-arm study is available and a comparative assessment is not possible.
• Overall, there is a hint of a non-quantifiable additional benefit for blinatumomab, as the scientific evidence does not permit quantification.
• Consequently, the G-BA classifies the extent of the additional benefit of blinatumomab in the present indication as non-quantifiable, based on the limited data available and in accordance with the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease is non-quantifiable.
• mortality
  • In the ALCANTARA study, the endpoint of overall survival was defined as the time from the first infusion of blinatumomab in the first treatment cycle until death from any cause.
  • At the final data cut-off, the median follow-up period was 25.1 months. Of the 45 patients included in the study, 37 (82.2 %) had died by this point.
  • As no comparative data are available, it is not possible to draw any conclusions regarding the extent of the additional benefit in the mortality category based on the results of the ALCANTARA study.
• Morbidity – Complete Remission
  • Complete remission was the primary endpoint in the ALCANTARA study. The endpoint was defined as the proportion of patients who achieved complete remission (CR) or complete remission with partial haematological recovery (CRh) within 2 treatment cycles.
  • In the ALCANTARA study, 14 (31.1 %) of the patients achieved CR, 16 (35.6%) of patients achieved CR or CRh, and 18 (40.0%) of patients achieved CR, CRh or CRi after the first two treatment cycles.
  • The endpoint of CR is an important prognostic factor and is relevant to treatment decisions. A CR associated with a reduction in disease symptoms that is noticeable to the patient is, in principle, relevant to the benefit assessment.
  • In the present study, CR/CRh was recorded in accordance with the criteria set out by Cheson et al. (2007), i.e. predominantly through blood and bone marrow tests. The endpoints were therefore not assessed on the basis of symptoms, but on the basis of laboratory tests.
  • There is no validation of CR as a surrogate parameter for other patient-relevant endpoints, e.g. mortality. Furthermore, it remains unclear whether achieving CRh has comparable clinical relevance to achieving CR. The CR/CRh endpoints are therefore classified in this review as endpoints of unclear relevance and are presented only as supplementary information.
• quality of life
  • No data on quality of life are available.
• Side effects – Total adverse events
  • The results are presented for supplementary purposes only. An adverse event occurred in all patients included in the study.
• Overall assessment / Conclusion
  • The benefit assessment of blinatumomab for the treatment of adult patients with Philadelphia chromosome-positive, CD19-positive, relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL), in whom treatment with at least two tyrosine kinase inhibitors (TKIs) has failed and who have no alternative treatment options, is based on the results of the ALCANTARA study.
  • Results are available for mortality, morbidity and adverse events.
  • Due to the single-arm design of the ALCANTARA study, a comparative assessment is not possible.
  • The propensity score-based comparison with the retrospective control study 20160462, as presented by the pharmaceutical manufacturer, is not taken into account. A particular limitation here is the definition of exposure in the control study, which results in relevant differences in the observation period for overall survival between the two studies. Further uncertainties include, amongst other things, a lack of information on patient characteristics and study centres, as well as relevant differences in patient characteristics (e.g. prior treatments). It cannot be assumed that all relevant confounders were adequately taken into account within the indirect comparison.
  • Furthermore, the evidence transfer from the TOWER study regarding quality of life and symptoms was rejected, as the pharmaceutical manufacturer had not provided sufficient proof of its generalisability.
  • Consequently, it is not possible to carry out a quantitative assessment of the extent of the effect or to quantify the additional benefit on the basis of the data submitted.
• Overall assessment / Conclusion
  • The benefit assessment of blinatumomab for the treatment of adult patients with Philadelphia chromosome-positive, CD19-positive, relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL), in whom treatment with at least two tyrosine kinase inhibitors (TKIs) has failed and who have no alternative treatment options, is based on the results of the ALCANTARA study.
  • Results are available for mortality, morbidity and adverse events.
  • Due to the single-arm design of the ALCANTARA study, a comparative assessment is not possible.
  • The propensity score-based comparison with the retrospective control study 20160462, as presented by the pharmaceutical manufacturer, is not taken into account. A particular limitation here is the definition of exposure in the control study, which results in relevant differences in the observation period for overall survival between the two studies. Further uncertainties include, amongst other things, a lack of information on patient characteristics and study centres, as well as relevant differences in patient characteristics (e.g. prior treatments). It cannot be assumed that all relevant confounders were adequately taken into account within the indirect comparison.
  • Furthermore, the evidence transfer from the TOWER study regarding quality of life and symptoms was rejected, as the pharmaceutical manufacturer had not provided sufficient proof of its transferability.
  • Consequently, it is not possible to carry out a quantitative assessment of the extent of the effect or to quantify the additional benefit on the basis of the data submitted.

Courtesy translation only, please refer to the German original.