Tisagenlecleucel (4) – Kymriah®

• Clinical trials
  • The JULIET registration trial is a single-arm Phase II trial being conducted at 27 centres worldwide.

Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), following two or more lines of systemic therapy

• Overall, for tisagenlecleucel in the treatment of adult patients with relapsed or refractory diffuse large B-celllymphoma following two or more lines of systemic therapy, as the scientific evidence does not permit quantification of a non-quantifiable additional benefit.
• mortality
  • The median follow-up period for overall survival was 5.9 months at the time of the current data cut-off.
  • In the ITT population, 59.3% of patients had died by this point, with a median survival of 8.2 months.
  • The Kaplan-Meyer estimator (KM estimator) in the JULIET study changes only slightly between study month 24 and study month 30.
• Morbidity – Overall response
  • Overall response (CR or PR) is the primary endpoint in the JULIET study.
  • From protocol version 4 onwards, it is operationalised using the 2014 Lugano Classification based on PET-CT or CT.
  • At the data cut-off date of 1 July 2019, the overall response rate in the ITT population was 35.9%.
• Morbidity – Progression-free survival
  • In the JULIET study, progression-free survival (PFS) is defined in the ITT population as the time from enrolment in the study until progression or recurrence, or until the patient’s death, regardless of the underlying cause of death.
  • As of the data cut-off date of 1 July 2019, 58.1% of patients had experienced such an event.
• Quality of life – FACT-Lym, SF-36
  • Health-related quality of life was assessed in the JULIET study using the FACT-Lym and SF-36 questionnaires.
  • The response rates for both questionnaires were below 70% during the course of the study, meaning they are considered unusable.
• Side effects
  • Adverse events were recorded in full from the start of lymphocyte-depleting chemotherapy until month 12 of the primary follow-up phase.
  • Within the first few weeks following the infusion, 85.2% of the ITT population experienced an AE Grade 3/4.
  • Serious AEs (SAEs) occurred in 48.7% of patients in the ITT population from the time of infusion up to week 8.
  • From week 9 to study month 12, 30.0% of patients experienced such an event.
  • Cytokine release syndrome occurred in 57.4% of patients treated with tisagenlecleucel.
• Overall assessment / Conclusion
  • Data on mortality, morbidity and side effects are available from the pivotal single-arm registration trial JULIET-1 for the benefit assessment.
  • Data on quality of life are also available. However, these show very minor response rates.
  • The indirect comparison carried out with the SCHOLAR-1 study is considered to have low validity due to a lack of information on relevant confounders and, consequently, insufficient adjustment.
  • Given the methodological uncertainties described with regard to adjustment, and the fact 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 data 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, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.