Tisagenlecleucel (7) – Kymriah®

• Clinical trials
  • The JULIET registration trial was a single-arm Phase II trial conducted at 28 centres worldwide from 2015 to 2022.
  • In addition, the dossier included data from the CCTL019B2401 registry study and the study by Bethge et al. (2022), based on the German Registry for Stem Cell Transplantation (DRST).

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

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification
• The certainty of the evidence is assessed overall as a hint.
• mortality
  • By the final data cut-off for the JULIET study on 22 December 2022, 107 participants had died.
  • The median survival time for the ITT population in the JULIET study, when combined with the LTFU data, is 8.2 months.
  • The Kaplan-Meier estimate is 41.0 at month 12 and 25.5 at 5 years after study enrolment.
  • Due to the high proportion of missing follow-up data for a major proportion of study participants, the overall survival data can only be considered valid up to month 60.
  • It is not possible to interpret or carry out a comparative assessment of the estimated survival time due to the lack of a control group.
• Morbidity – Overall Response Rate (ORR)
  • The overall response rate was the primary endpoint in the JULIET study and was defined as the proportion of patients achieving CR or PR from the time of infusion until disease progression or the start of a new anti-tumour therapy (including stem cell transplantation), whichever occurred first.
  • Overall, at the final data cut-off for the JULIET study, 26.9% (as assessed by the IRC) and 23.4% (as assessed by the medical study staff) of participants in the ITT population achieved a complete response.
• Morbidity – Progression-free survival (PFS)
  • In the ITT population, PFS was defined as the time from enrolment in the study until progression/recurrence or until the patient’s death, regardless of the underlying cause of death.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
  • The PFS endpoint is presented for supplementary information.
• Morbidity – Event-Free Survival (EFS)
  • In the JULIET study, EFS was defined as the time from the tisagenlecleucel infusion (for the ITT population, the time from enrolment in the study) until progression/recurrence, until the start of a new lymphoma treatment (excluding stem cell transplantation) or until the patient’s death, regardless of the underlying cause of death.
  • The dossier contains no data on the qualifying events for the EFS endpoint.
  • EFS is therefore not taken into account in this benefit assessment.
• 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 all post-baseline measurements were < 70% relative to the infusion group (which does not correspond to the ITT).
  • The data are considered unusable.
• Side effects
  • During the study period between the start of treatment (start of lymphocyte-depleting chemotherapy) and study month 12, adverse events (AEs) and serious AEs (SAEs) were recorded in full, provided that the patients remained in the primary follow-up phase.
  • Within the first few weeks following the infusion, 85.2% of the ITT population experienced a CTCAE Grade 3/4 AE.
  • From study week 9 to study month 12, 51% were affected by such an event.
  • SAE 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% of patients experienced such an event.
  • The most common SAE and one of the most common Grade 3 or 4 AEs is cytokine release syndrome. It occurred in 57.4% of patients treated with tisagenlecleucel.
  • Due to the single-arm study design, a comparative assessment of side effects is not possible.
• Overview
  • Final data on mortality, morbidity, quality of life and side effects, as well as data from long-term follow-up, are available from the single-arm pivotal registration trial JULIET.
  • As no comparative data are available, no conclusion can be drawn from these results regarding the extent of the additional benefit.
  • The overall assessment concludes that there is a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.