Blinatumomab (9) – Blincyto®

• Clinical trials
  • The E1910 trial is an ongoing, randomised, controlled, open-label study investigating the efficacy and safety of blinatumomab monotherapy alternating with chemotherapy (4+4=8 cycles) compared with chemotherapy alone (4 cycles) in adult patients with newly diagnosed BCR/ABL-negative B-cell progenitor ALL as part of consolidation therapy.

Adults with newly diagnosed Philadelphia chromosome-negative, CD19-positive B-cell progenitor ALL; consolidation therapy

• On balance, the G-BA has established that blinatumomab offers considerable additional benefit for patients with newly diagnosed Philadelphia chromosome-negative, regarding overall survival and free from recurrence survival, CD19-positive B-cell progenitor ALL as part of consolidation therapy.
• Overall, the G-BA derives a hint of the established additional benefit from the strength of the evidence.
• mortality
  • Overall survival is defined as the period from the time of randomisation until death from any cause.
  • For the endpoint of overall survival, there is a statistically significant difference in favour of blinatumomab alternating with chemotherapy compared with chemotherapy alone.
  • At the time of the current data cut-off, 30 patients (19.7 %) in the blinatumomab arm and 53 patients (39.6 %) in the chemotherapy arm had died.
  • The median survival time has not yet been reached in either treatment arm.
  • The extent of the prolongation in overall survival achieved is regarded as a significant improvement.
• Morbidity – Recurrence-free survival
  • The endpoint recurrence-free survival (RFS) is defined as the time from randomisation/enrolment in Step 3 until the time of recurrence or death from any cause.
  • For the recurrence-free survival endpoint, there is a statistically significant difference in favour of blinatumomab alternating with chemotherapy compared with chemotherapy alone.
  • The median time to event has not yet been reached.
  • The extent of the prolongation in recurrence-free survival achieved is considered a significant improvement.
  • However, there are uncertainties as to the extent to which the curative treatment goal can be considered achieved as early as after the intensification phase and before the consolidation phase begins.
• quality of life
  • No data on quality of life were collected.
• Side effects
  • In the E1910 study, complete data collection was carried out only for severe adverse events (AEs) of CTCAE grade ≥ 3, with the exception of ‘blood and lymphatic system disorders’ and ‘metabolic and nutritional disorders’ – for which only CTCAE Grade 4 and 5 AEs were recorded – as well as for AEs of particular interest.
  • Consequently, no data are available for the total number of AEs or for serious SAEs.
  • Only a selective collection of individual AEs, regardless of severity, and SAEs was envisaged.
  • ‘Expedited AEs’ were classified according to CTCAE version 5.0. However, these are AEs that were, in some cases, selectively defined and recorded for only one treatment group at a time.
  • Furthermore, a survey of AEs was described that were considered to have a possible, probable or proven association with the study medication. This is regarded as invalid.
  • No data on the median observation period for AEs were provided.
  • Due to the alternating administration of chemotherapy, which is associated with numerous adverse events, there is uncertainty as to whether a time-to-event analysis would be less biased in this case than the RR.
  • Given the longer duration of treatment in the intervention arm compared with the control arm (alternating administration of chemotherapy with blinatumomab), a time-to-event analysis may, in principle, be more appropriate than the relative risk analysis carried out.
  • Severe AEs (CTCAE grade ≥ 3)
  • No significant difference was observed for the endpoint of severe AEs.
  • Discontinuation due to AEs
  • No data could be identified regarding the complete recording of AEs that led to discontinuation of the study medication.
  • It is unclear to what extent AEs leading to therapy discontinuation were fully recorded.
  • However, discontinuation of treatment due to an AE is described in some cases for AEs of CTCAE grade ≥ 3.
  • Furthermore, it is unclear whether AEs attributable to the underlying condition were taken into account.
  • Overall, the data are considered unevaluable.
  • Specific AEs
  • In the E1910 study, a significant disadvantage compared to blinatumomab was observed for the endpoints ‘nervous system disorders’ (severe AEs) and ‘neurological events’ (adverse events of particular interest).
  • For the endpoint ‘low white blood cell count’ (severe AE), a significant advantage in favour of blinatumomab was observed.
  • In the overall review of the results on side effects, no data are available for SAEs and no suitable data are available for therapy discontinuations due to AEs.
  • For severe AEs, there is no statistically significant difference between the treatment arms.
  • In detail, the specific AEs predominantly show disadvantages.
• Overall assessment
  • For the benefit assessment, results on mortality, morbidity and side effects are available from the ongoing, randomised, controlled, open-label E1910 trial comparing blinatumomab monotherapy alternating with chemotherapy versus chemotherapy alone.
  • For the endpoint of overall survival, there is a significant advantage in favour of blinatumomab. The extent of the prolongation in overall survival achieved is assessed as a marked improvement.
  • For the recurrence-free survival endpoint, there is a statistically significant difference in favour of blinatumomab. The extent of the prolongation in recurrence-free survival achieved is assessed as a marked improvement.
  • No data are available for the quality of life endpoint category.
  • For the endpoint category ‘side effects’, data are available only for severe AEs (CTCAE grade ≥ 3), AE of CTCAE grades 4 and 5 (SOC ‘Blood and lymphatic system disorders’ and ‘Metabolic and nutritional disorders’) and for AE of particular interest.
  • For severe AEs, there is no statistically significant difference between the treatment arms. In detail, the specific AEs predominantly show disadvantages.
  • Overall, the G-BA concludes that, based on clear advantages in overall survival and relapse-free survival, blinatumomab offers considerable additional benefit for patients with newly diagnosed Philadelphia chromosome-negative, CD19-positive B-cell progenitor ALL as part of consolidation therapy.

Courtesy translation only, please refer to the German original.