Blinatumomab (2) – Blincyto®

• Clinical trials
  • For the renewed benefit assessment of the active ingredient blinatumomab, the pharmaceutical manufacturer submitted the randomised, open-label, multicentre Phase III trial 00103311 (TOWER).

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

• mortality
  • Overall survival was assessed as the primary endpoint in the TOWER study and was defined as the period from randomisation until death from any cause or until the last follow-up date.
  • Treatment with blinatumomab resulted in a statistically significant prolongation of overall survival compared with standard-of-care (SOC) chemotherapy (hazard ratio (HR) 0.71; 95% confidence interval (CI) [0.55; 0.93]; p = 0.012).
  • The median survival time was 7.7 months in the blinatumomab arm and 4.0 months in the control arm. Blinatumomab therefore prolonged the median survival time by 3.7 months.
  • Overall, blinatumomab achieves a moderate improvement in overall survival compared with treatment with standard-of-care (SOC) chemotherapy.
• Morbidity – Complete remission (CR, CR/CRh/CRi)
  • Complete remission (CR) within the first two treatment cycles was achieved by 91 patients (33.6%) in the blinatumomab arm and by 21 patients (15.7%) in the SOC chemotherapy arm. Treatment with blinatumomab resulted in a statistically significant increase in the complete remission (CR) rate compared with treatment with SOC chemotherapy (relative risk (RR) 2.14; 95% CI [1.40; 3.28]; p < 0.001).
  • For the composite endpoint comprising the CR rate, the rate of complete remission with partial haematological recovery (CRh) and the rate of complete remission with incomplete recovery of the peripheral blood count (CRi), a statistically significant advantage in favour of blinatumomab treatment was also observed (RR 1.78; 95% CI [1.29; 2.47]; p < 0.001). Complete remission during the first two treatment cycles, as defined by the combined endpoint of CR/CRh/CR, was achieved by 119 patients (43.9%) receiving blinatumomab and 33 patients (24.6%) receiving standard-of-care (SOC) chemotherapy.
  • As post-baseline data on CR/CRh/CRi were missing for 68 patients (25.1 %) in the blinatumomab arm and 65 patients (48.5%) in the standard-of-care (SOC) chemotherapy arm, post-baseline data on CR/CRh/CRi were missing; these patients were therefore assumed to have failed to respond, and the values were imputed accordingly by the pharmaceutical manufacturer. Due to the data imputation, a potential bias in the results in favour of blinatumomab cannot be ruled out.
  • Sensitivity analyses considering only those patients for whom post-baseline values for CR and CR/CRh/CRi were available show a statistically significant advantage in favour of blinatumomab for the CR endpoint (p = 0.013).
  • The endpoints CR and CR/CRh/CRi are therefore classified in this assessment as endpoints of unclear relevance and are presented only as supplementary information. No conclusion can be drawn regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life was assessed using the cancer-specific EORTC QLQ-C30 questionnaire.
  • As the response rates are comparable to those for the symptom scales of the EORTC QLQ-C30, the results for health-related quality of life are, in line with the comments in the ‘Symptoms’ section, not considered usable overall.
• Side effects
  • Adverse events (AEs) occurred in almost all study participants. The treatment durations differed significantly between the blinatumomab arm (89.0 years) and the standard-of-care (SOC) chemotherapy arm (14.8 years). A comparison of AEs between the treatment arms is therefore subject to bias against blinatumomab.
  • Based on the unadjusted event rates, there are statistically significant disadvantages associated with treatment with blinatumomab in the categories of serious AEs and infusion reactions. This is offset by statistically significant advantages for blinatumomab in the case of the AEs neutropenia and cytopenia.
  • In view of the significant differences in treatment durations between the treatment arms, additional analyses (exposure-time-adjusted incidence rates), which take treatment duration into account at patient level, were included for severe AEs (CTCAE grade ≥ 3), SAE and AEs leading to therapy discontinuation.
  • The results of the exposure-adjusted analysis of AEs at the patient level show statistically significant advantages for blinatumomab in terms of severe AEs, SAE and AEs leading to therapy discontinuation.
  • In summary, both the results based on unadjusted event rates and the exposure-adjusted data at patient level show serious biases, which, taken together, mean that a definitive assessment of the available data on AEs is not possible.
• Overall assessment
  • For the re-assessment of the benefits of blinatumomab in the treatment of adults with Philadelphia chromosome-negative, relapsed or refractory B-progenitor acute lymphoblastic leukaemia, results are available for the endpoint categories of mortality (overall survival), morbidity, quality of life and side effects from the TOWER trial, in which blinatumomab was compared with standard-of-care chemotherapy.
  • With regard to overall survival, blinatumomab resulted in a moderate prolongation of median survival of 3.7 months (7.7 months vs. 4.0 months).
  • It was not possible to assess morbidity and health-related quality of life, as the proportion of patients for whom no data are available was already very high at early analysis time points. It is therefore not possible to assess how blinatumomab affects disease-specific symptoms and patients’ health-related quality of life.
  • Based on the available data on adverse events, it is generally unlikely that blinatumomab would have a disadvantage compared with standard-of-care chemotherapy. However, the available data on adverse events show biases that do not allow for a definitive assessment.
  • Overall, a significant improvement in treatment-related benefit—unprecedented to date—has been observed, as a moderate prolongation of survival has been achieved without any disadvantages in terms of side effects. Uncertainties remain due to a lack of meaningful data on morbidity and quality of life.

Courtesy translation only, please refer to the German original.