Blinatumomab (1) – Blincyto®

• Clinical trials
  • This study is a single-arm, multicentre, open-label Phase II trial.
  • The results of the registration trial MT103-211 are available to address the question regarding the extent of the additional benefit.

Adults with Philadelphia chromosome-negative, relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL)

• For adult patients with Philadelphia chromosome-negative, relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL), there is an additional benefit, but it is non-quantifiable because the current scientific evidence does not permit this.
• The G-BA classifies the extent of the additional benefit of blinatumomab as non-quantifiable on the basis of 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 the treatment of the disease.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• In the present case and for this indication, the lack of a control group in the MT103-211 study and the lack of validity of the historical control provided are relevant to the decision.
• mortality
  • In the MT103-211 study, ‘overall survival’ is assessed as a secondary endpoint.
  • In the primary analysis set of this study, 116 of the 189 patients (61.4 %) had died by the date of the last follow-up.
  • The median overall survival was 6.1 months with a median follow-up period of 9.8 months (95% CI: [7.1; 12.0]).
  • The one-year survival probability was 27.9% (95% CI: [20.3; 36.1]).
  • The mortality endpoint in the MT103-211 study is considered valid.
• Morbidity – complete remission (CR)
  • In the registration trial MT103-211, 81 patients (42.9%) achieved the primary endpoint of complete remission (CR) / complete remission with partial haematological recovery (CRh).
  • Complete remission (CR), associated with a reduction in disease symptoms that is noticeable to the patient, is relevant to patients; however, symptoms were not recorded in this case.
  • Nor is there any validation of CR as a surrogate marker for other patient-relevant endpoints, such as mortality.
  • The endpoint ‘complete remission’ is an important prognostic factor and relevant to treatment decisions.
  • However, the primary endpoint selected in the MT103-211 study does not take into account the duration of the response.
  • Furthermore, it is unclear whether achieving CRh has comparable clinical relevance to achieving CR.
  • In the assessment, the primary endpoint was classified as an endpoint of unclear relevance and presented as supplementary information.
• Morbidity – MRD response rate
  • Within two treatment cycles with blinatumomab, 65 patients (34.4%) achieved an MRD response and 53 patients (28.0%) achieved a complete MRD response.
  • No MRD data were available for 8 patients. These patients were included in the analysis as non-responders.
  • Achieving MRD negativity is regarded as an important prognostic factor in the treatment of ALL, and studies have demonstrated an association between MRD negativity and relapse or mortality; however, no studies are available for the patient population with r/r B-precursor ALL.
  • There is no formal validation of MRD negativity as a surrogate marker for survival.
  • In the assessment, MRD negativity was classified as an endpoint of unclear relevance and presented as supportive evidence.
  • It is unclear to what extent this endpoint allows conclusions to be drawn about treatment effects.
  • No conclusions can be drawn regarding the extent of the additional benefit.
• quality of life
  • Quality of life was not assessed in the MT103-211 study.
  • Consequently, no data are available to assess the additional benefit of blinatumomab in terms of quality of life.
• Side effects
  • Adverse events occurred at least once in almost all patients.
  • AE of particular interest that occurred after the start of treatment were neurological events (51.9%), infections (63.0%), infusion reactions (28.6%), CRS (12.7%), tumour lysis syndrome (4.2%), medication errors (3.2%), elevated liver enzyme levels (27.5%), neutropenia and febrile neutropenia (42.9%), reduced immunoglobulin levels (11.1%) and capillary leak syndrome (0.5%).
  • In 63 patients (33.3%), an AE led to treatment interruption, most commonly due to neurological side effects.
  • In the regulatory authority’s safety assessment, an indication was given that long-term safety data for blinatumomab from the MT103-211 trial were available for only 12 patients.
  • In total, only 10 patients had received 2 cycles of initial therapy plus a further 3 cycles of consolidation therapy.
  • The risk associated with long-term therapy was determined as part of an analysis of AEs over the duration of exposure. There was no evidence of an increased risk with longer duration of exposure.
  • However, the validity of the analysis was rated as minor due to the very small patient population studied.
  • The potential for harm associated with blinatumomab cannot currently be validly assessed.
  • Consequently, no conclusion can be drawn regarding the extent of the additional benefit in terms of side effects.
• Overall assessment / Conclusion
  • Taking an overall view of the available results, the G-BA, based on the marketing authorisation and the desired and undesired effects observed in the aforementioned study, and taking into account the comments received, the oral hearing and the severity of the disease, the G-BA arrives at the following assessment of the extent of the additional benefit:
  • There is an additional benefit, but it is non-quantifiable because the available scientific data do not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.
• Overall assessment / Conclusion
  • Taking an overall view of the available results, the G-BA, based on the marketing authorisation and the desired and undesired effects observed in the aforementioned study, and taking into account the comments received, the oral hearing and the severity of the condition, the G-BA arrives at the following assessment of the extent of the additional benefit:
  • There is an additional benefit, but it is non-quantifiable because the available scientific data do not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.

Courtesy translation only, please refer to the German original.