Tisagenlecleucel (6) – Kymriah®

• Clinical trials
  • The ELIANA trial is the pivotal registration trial for tisagenlecleucel in this therapeutic indication. The ELIANA trial is a single-arm, multicentre, uncontrolled Phase II trial, which was conducted at 23 trial centres worldwide between 2015 and 2022.
  • The ENSIGN study is a single-arm, multicentre, uncontrolled Phase II study, which was originally submitted as a supportive study as part of the regulatory approval process.
  • The B2001X study is a single-arm, multicentre Phase IIIb study designed to ensure access to treatment with tisagenlecleucel following the completion of the ELIANA and ENSIGN studies.

Children, adolescents and young adults up to and including the age of 25 with refractory or relapsed (relapse following transplantation or second or subsequent relapse) acute lymphoblastic B-cell leukaemia (ALL)

• Overall, there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• The certainty of the findings is assessed overall as a hint.
• mortality
  • Based on the ITT population, the median survival is 47.6 months for the ELIANA study, 28.5 months for the ENSIGN study and 54.7 months for the B2001X study. The data from the long-term A2205B study are included in these figures.
  • Based on the Kaplan-Meier estimator, only a slight change is observed for the ELIANA study between study month 48 and study month 60. For the ENSIGN study, the estimator remains constant.
  • Due to the single-arm study design, a comparative assessment of mortality is not possible.
• Morbidity – Response (CR/CRi)
  • Response was defined in the tisagenlecleucel studies using predefined criteria based on those set out by Cheson et al. in 2003. The assessment was carried out by an independent review committee. A response was only classified as such if it had persisted for at least 28 days.
  • A response within 6 months was observed in 68.4% of patients in the ELIANA trial, 60% of patients in the ENSIGN trial and 77% of patients in the B2001X trial.
• Morbidity – MRD remission
  • A negative MRD status is defined in the present studies as fewer than 110⁻⁴ (<0.01%) mononuclear cells in the bone marrow. MRD status was determined in patients who had previously achieved remission following tisagenlecleucel infusion.
  • MRD remission rates were 67.3% (ELIANA), 57.3% (ENSIGN) and 40.5% (B2001X), respectively.
• Morbidity – Relapse-free survival (RFS)
  • Recurrence-free survival (RFS) is defined in the tisagenlecleucel studies as the time from achieving remission (CR/CRi) until the occurrence of a relapse or death from any cause.
  • In the ENSIGN trial, the median RFS had not yet been reached; in the B2001X trial, it was 51.4 months; and in the ELIANA trial, it was 46.8 months.
  • Due to the single-arm study design, a comparative assessment of RFS is not possible.
• Morbidity – Event-Free Survival (EFS)
  • Event-free survival (EFS) is defined in the tisagenlecleucel studies as the time from enrolment in the study until the occurrence of a relapse, death from any cause following remission (CR/CRi) or treatment failure.
  • The dossier contains no data on the qualifying events for the EFS endpoint. EFS is therefore not taken into account in this benefit assessment. Irrespective of this, a comparative assessment of the data is not possible due to the single-arm study design.
• 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. As the response rates are below 70 per cent, the data are classified as unusable.
• quality of life
  • Data on quality of life were collected in the ELIANA study using the PedsQL questionnaire. The questionnaire comprises four multidimensional scales (physical functioning, emotional functioning, social functioning and academic functioning) and three summary scores (overall score, physical health summary score; psychosocial health summary score).
  • As the response rates are below 70%, the data are classified as unusable.
• Side effects
  • Adverse events (AEs) were fully recorded from the start of the lymphocyte-depleting chemotherapy until study month 12 of the primary follow-up phase.
  • Across all three studies, the highest rates of serious AEs (CTCAE Grade 3/4) and severe AEs (SAE) occurred in the period between the tisagenlecleucel infusion and study week 8 (severe AEs: 83.8% (ELIANA)/ 84.4% (ENSIGN)/ 72.5% (B2001X); SAE: 67.5% (ELIANA)/ 71.9% (ENSIGN)/ 56.5% (B2001X)).
  • Due to the single-arm study design, a comparative assessment of side effects is not possible.
• Overall assessment
  • Final data on mortality, morbidity, quality of life (ELIANA only) and side effects are available from the single-arm pivotal registration trial ELIANA and the single-arm supportive trials ENSIGN and B2001X.
  • The indirect comparison carried out is deemed invalid due to insufficiently documented positivity, the inadequate consideration of confounders classified as ‘important’ and ‘very important’ in the analysis, and the use of the ATT estimator; the resulting effect estimators are therefore deemed uninterpretable.
  • Due to the single-arm study design, a comparative assessment of the endpoints relating to mortality, morbidity and side effects is not possible. Furthermore, the data on the EQ-5D VAS and health-related quality of life are not usable due to the low response rates.
  • Overall, a non-quantifiable additional benefit is identified, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.