Blinatumomab (3) – Blincyto®

• Clinical trials
  • The single-arm Phase II trial MT103-205 was decisive for the marketing authorisation.
  • MT103-205 is an uncontrolled, multicentre Phase I/II trial investigating the efficacy and safety of blinatumomab in paediatric and adolescent patients with relapsed or refractory B-precursor cell ALL.
  • The pharmaceutical manufacturer also cites study 00103311 (TOWER) to support the evidence transfer from adult patients to the paediatric patients under assessment. This is a randomised, controlled trial in adult ALL patients, which also formed the basis for the benefit assessment of 7 December 2017.

Paediatric patients aged 1 year or older with Philadelphia chromosome-negative, CD19-positive B-progenitor ALL, which is refractory or has relapsed following at least two previous lines of treatment, or has relapsed following a previous allogeneic haematopoietic stem cell transplant

• Consequently, the G-BA classifies the extent of the additional benefit of blinatumomab in this indication as unquantifiable, given the limited data available, 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 treating the disease, as non-quantifiable.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • By the end of the study, 68.8% of the 70 study patients treated with blinatumomab had died.
  • The median survival time was 7.5 months.
• Morbidity – Complete remission
  • In study MT103-205, complete remission was defined as achieving a blast proportion in the bone marrow of less than 5 per cent, in conjunction with the absence of circulating blasts or extramedullary disease, as well as the achievement of bone marrow status M1 with complete recovery of the peripheral blood count.
  • Overall, as of the data cut-off date of 12 January 2015, 38.6% of patients achieved complete remission within the first two cycles of blinatumomab.
  • The CR endpoint is an important prognostic factor and is relevant to treatment decisions for this indication. A CR associated with a reduction in disease symptoms that is perceptible to the patient is, in principle, relevant to the patient during benefit assessment. In this case, the endpoint was assessed not 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. In this assessment, the endpoint is classified as one of unclear relevance and is presented only as supplementary information. No conclusion can be drawn regarding the extent of the additional benefit.
• Morbidity – MRD remission
  • Fifteen patients in study MT103-205 achieved molecular complete remission within the first two treatment cycles, defined as a reduction in leukaemia cells to less than 10⁻⁴.
  • Achieving MRD negativity is regarded as an important prognostic factor in the treatment of ALL. Studies have also demonstrated an association between MRD negativity and relapse or mortality. There is no validation of MRD negativity as a surrogate parameter for overall survival. The endpoint is therefore presented for supplementary information. No conclusions regarding the extent of the additional benefit are drawn from the results.
• Side effects
  • Adverse events were recorded in the MT103-205 study from the start of treatment until 30 days after the last blinatumomab infusion, the end of the study or the start of follow-up therapy. During the follow-up period, only treatment-related side effects were recorded.
  • All study patients experienced an adverse event (AE) during the observation period. 87.1% of patients experienced an AE with a severity of ≥ 3 according to the CTCAE; 55.7% of patients experienced a serious adverse event (SAE). Four of the 70 patients in the full-analysis-set population had to discontinue the study medication due to an adverse event.
  • With regard to AEs with a severity grade of ≥ 3 according to CTCAE, the following occurred at the Preferred Terms level: anaemia, thrombocytopenia, febrile neutropenia, leucopenia, neutropenia, cytokine release syndrome, hypokalaemia, hypertension, pyrexia, as well as elevated levels of alanine and aspartate aminotransferases, and furthermore low neutrophil, platelet and white blood cell counts, with a frequency of more than 5 per cent. For SAE, this applies to the side effects of febrile neutropenia, cytokine release syndrome and pyrexia.
• Overall assessment
  • For the benefit assessment of blinatumomab in the treatment of paediatric ALL patients, results are available for the endpoint categories of mortality, morbidity and side effects from the uncontrolled clinical study MT103-205.
  • The available historical data are not suitable for either a naive or a propensity-score-matched indirect comparison and are considered unsuitable for demonstrating additional benefit, particularly due to insufficient information on the study populations and uncertainties regarding the adjustment method used.
  • Due to the single-arm study design and the unsuitable historical control, a comparative assessment of the study results is not possible overall. Furthermore, evidence transfer is not appropriate.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit based on the data presented are also not possible.

Courtesy translation only, please refer to the German original.