Blinatumomab (4) – Blincyto®

• Clinical trials
  • The single-arm, multicentre Phase II trial MT103-203 (BLAST) was decisive for the marketing authorisation of blinatumomab for this indication.

Adult patients with Philadelphia chromosome-negative, CD19-positive B-precursor ALL in first or second complete remission with a minimal residual disease (MRD) of at least 0.1%

• Consequently, the G-BA classifies the extent of the additional benefit of blinatumomab for this indication as ‘not quantifiable’ on the basis of the limited data available, 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, 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
  • As of the final data cut-off on 7 January 2019, 56.4% of the 110 study patients treated with blinatumomab had died.
  • The median survival time was 36.5 months.
  • The median follow-up period was 59.8 months.
  • The Kaplan-Meier estimate changes only slightly between month 48 and month 60. The estimate at 60 months is 0.43.
• Morbidity – MRD negativity
  • A molecular complete remission following the first treatment cycle, defined as the absence of detectable leukaemia-specific rearrangements of the immunoglobulin or TCR genes by PCR (sensitivity of at least 10⁻⁴), was achieved by 77.9% of patients in the MT103-203 study.
  • 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 as supplementary information. No conclusions regarding the extent of the additional benefit are drawn from the results.
• Morbidity – EQ-5D VAS
  • The health status data, collected using the EQ-5D visual analogue scale, changed by an average of 4.33 points in the 103 patients included in the analysis between the baseline assessment and the end of the first treatment cycle.
  • The absolute median change was 2.00 scale points.
  • Response rates were above 70% only at baseline and after treatment cycle 1; therefore, further assessment time points are not shown.
• Morbidity – EORTC QLQ-C30 symptom scales
  • Response rates for the EORTC QLQ-C30 were also above 70% only at baseline and after treatment cycle 1.
  • With regard to the symptom scales covered by the EORTC QLQ-C30, none of the symptoms (fatigue, nausea and vomiting, pain, shortness of breath, insomnia, loss of appetite, constipation, diarrhoea) showed a change in the mean score of more than 3 scale points.
  • The median change for all symptom scales was 0 points.
• Health-related quality of life – EORTC QLQ-C30 functional scales
  • For none of the functional scales relating to general health status, physical functioning and cognitive functioning was there a change of more than 4.2 scale points on average when comparing the baseline assessment with the assessment following completion of the first blinatumomab cycle.
  • The mean change for social functioning was 10.42 points.
  • The median change for all functional scales was 0 points.
  • Here too, response rates were above 70% only at baseline and after treatment cycle 1.
• Side effects
  • Adverse events were recorded in the MT103-203 study from the start of treatment until 30 days after the last blinatumomab infusion or the end of the study.
  • All study patients experienced an adverse event during this period.
  • 61.2% of patients experienced an AE with a severity of ≥ 3 according to the CTCAE; 62.9% of patients experienced a serious SAE.
  • 17.2% of patients discontinued the study medication due to an adverse event.
  • With regard to AEs with a severity of ≥ 3 according to the CTCAE, the following Preferred Terms occurred with a frequency of more than 5 per cent: leucopenia and neutropenia, fever, tremor, and elevated alanine aminotransferase levels.
  • For the SAE, this applies to the side effects fever, encephalopathy, tremor and aphasia.
• Overall assessment
  • Results are available for the benefit assessment of blinatumomab for the treatment of adults with Philadelphia chromosome-negative, CD19-positive B-progenitor ALL in first or second complete remission with a minimal residual disease (MRD) of at least 0.1 per cent, results are available for the endpoint categories of mortality, morbidity, quality of life and side effects from the uncontrolled MT103-203 clinical study.
  • The historical data from study 20120148 submitted by the pharmaceutical manufacturer are not suitable for either a naive or a propensity-score analysis, and are considered unsuitable for demonstrating additional benefit, particularly due to insufficient information on the study population and the resulting questionable comparability, as well as 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.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit on the basis of the data provided are also not possible.

Courtesy translation only, please refer to the German original.