Tisagenlecleucel (3) – Kymriah®

• Clinical trials
  • The ELIANA study is a pivotal registration trial. The ELIANA study is a single-arm, multicentre, uncontrolled Phase II trial being conducted at 23 study centres worldwide.
  • The ENSIGN trial is a single-arm, multicentre, uncontrolled Phase II trial, which was originally submitted as a supportive study as part of the regulatory approval process.
  • The MT103-205 study is a single-arm, multicentre, uncontrolled Phase I/II study.

Children, adolescents and young adult patients aged up to and including 25 years with refractory or relapsed (relapse following transplantation or second or subsequent relapse) acute lymphoblastic B-cell leukaemia (ALL)

• Hint for a non-quantifiable additional benefit, as the available scientific data do not permit quantification
• Overall, for tisagenlecleucel in the treatment of children, adolescents and young adults aged up to and including 25 years with refractory or relapsed acute lymphoblastic B-cell leukaemia, as the scientific evidence does not permit quantification of a non-quantifiable additional benefit.
• Mortality – Overall survival
  • Based on the ITT population, 45.6% of patients in the ELIANA trial had died by the data cut-off date of 1 July 2019, and 48% of patients in the ENSIGN trial had died by the data cut-off date of 24 May 2019.
  • In the ELIANA study, the median overall survival had not yet been reached at this data cut-off (median follow-up of 24.9 months). In the ENSIGN study, the median overall survival at this point (median follow-up of 13.6 months) was 25.9 months.
  • As no comparative data are available, no conclusions can be drawn from these results regarding the extent of the additional benefit.
• Morbidity – Response (CR/CRi)
  • Response was defined in the ELIANA and ENSIGN studies using predefined criteria based on those set out by Cheson et al. (2003) and the NCCN guidelines (version 1.2013).
  • At 6 months, 60% of the ITT population in the ENSIGN study showed a response, compared with 68% in the ELIANA study.
• Morbidity – Recurrence-free survival (RFS)
  • Recurrence-free survival was defined in both studies as the time from achieving remission/response until the occurrence of a recurrence or death from any cause.
  • Based on the available data, events classified as relapse occurred in 36.4% of patients in the ELIANA study and in 28.9% of patients in the ENSIGN study who had achieved a response.
• Morbidity – Health status
  • Health status was assessed in the ELIANA study using the EQ-5D VAS (visual analogue scale).
  • The assessment was carried out only in patients who were at least 8 years old. Even when considering only this patient group, the questionnaire response rate was over 70% only at the time of screening. The data are therefore not classified as usable.
• Quality of life – health-related quality of life
  • Data on quality of life were collected in the ELIANA study using the PedsQL questionnaire.
  • Data were collected only from patients aged 8 years or older. Even when considering this patient group exclusively, the questionnaire response rate remained consistently below 70% throughout the entire study period. The data are therefore not considered usable.
• Side effects
  • Within the first few weeks following infusion, a CTCAE Grade 3/4 adverse event occurred in 83.5% of patients in the ELIANA study and 84.4% of patients in the ENSIGN study.
  • Serious adverse events occurred in 68.4% and 71.9% of patients, respectively, in the studies during the period from the time of infusion up to and including study week 8.
  • The AEs of particular interest, ‘cytokine release syndrome’, were experienced by 77.2% of patients in the ELIANA study and 78.1% of patients in the ENSIGN study.
• Overall assessment / Conclusion
  • Data on mortality, morbidity and side effects are available from the pivotal registration trial ELIANA and the supportive trial ENSIGN.
  • Data on quality of life are also available. However, these show very minor response rates.
  • Given that there are methodological uncertainties regarding the adjustment in the indirect comparisons and that the effect estimate is not of a magnitude from which an actual effect can be inferred whilst taking these uncertainties into account, the available results cannot be used to determine the extent of the additional benefit.
  • In summary, the available results are, on the whole, classified as non-quantifiable in terms of their extent, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.