Tisagenlecleucel (5) – Kymriah®

• Clinical trials
  • For the benefit assessment, the results of the single-arm, multicentre Phase II ELARA trial, which formed the basis for marketing authorisation, were presented in the dossier.
  • Furthermore, to derive the additional benefit, the pharmaceutical manufacturer presented an indirect comparison, without a bridge comparator, between the ELARA study and the RECORD-FL study.

Adults with relapsed or refractory follicular lymphoma (FL) following two or more lines of systemic therapy

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• As only single-arm data are available and a comparative assessment is not possible, the certainty of the findings is rated as a hint.
• mortality
  • Overall survival was defined in the ELARA study as the time from the tisagenlecleucel infusion to death from any cause.
  • 10.2% of patients in the enrolled set (n = 98) had died by the data cut-off date (median follow-up duration 19.5 months). The Kaplan-Meier estimate at month 18 is 93.2%.
  • Due to the single-arm study design, a comparative assessment of the mortality data is not possible.
• Morbidity – Complete remission rate
  • The complete remission rate, assessed by an independent review committee (IRC), is the primary endpoint of the ELARA study.
  • 68.3% of patients in the enrolled set were shown to have achieved complete remission as assessed by the IRC at the time of data cut-off.
  • Notwithstanding this, a comparative assessment of the morbidity data is not possible due to the single-arm study design.
• Morbidity – Health status (EQ-5D VAS)
  • General health status was assessed in the ELARA study using the European Quality of Life 5 Dimensions visual analogue scale.
  • The available data on health status collected using the EQ-5D VAS are therefore not considered usable.
• Quality of life – FACT-Lym
  • Disease-specific quality of life was assessed using the validated Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) questionnaire.
  • With regard to the survey based on the enrolled set, the time interval between the first and second surveys, and the response rates, please refer to the relevant comments on the EQ-5D VAS.
  • The available data on quality of life collected using FACT-Lym are therefore not considered usable.
  • Notwithstanding this, a comparative evaluation of the quality of life data is not possible due to the single-arm study design.
• Quality of life – SF-36
  • Furthermore, quality of life was assessed using the validated generic Short Form (SF)-36 questionnaire.
  • With regard to the data collection based on the enrolled set, the time interval between the first and second assessments, and the response rates, please refer to the relevant comments on the EQ-5D VAS.
  • The available data on quality of life collected using the SF-36 are therefore not considered usable.
• Side effects
  • Almost all patients experienced an AE during the course of the study, with the majority, as expected, occurring within the 8 weeks following infusion of tisagenlecleucel.
  • During this period, 71.1% of patients experienced an AE of grade ≥ 3 (according to CTCAE or, for cytokine release syndrome, according to Lee et al. 2014), whilst 27.8% experienced a serious adverse event (SAE).
  • Subsequently, up to 1 year after infusion, 44.8% of patients experienced an AE of grade ≥ 3 and 20.8% experienced a SAE.
  • Among the AESI, the most common events occurring in all phases following infusion were haematological disorders, including cytopenia (in 75.3% of patients within 8 weeks of infusion) and cytokine release syndrome (in 48.5% of patients within 8 weeks of infusion).
  • Due to the single-arm study design, a comparative assessment of the data on side effects is not possible.
• Overall assessment / Conclusion
  • Data for the benefit assessment are available from the single-arm, multicentre Phase II ELARA trial, which formed the basis for marketing authorisation. Furthermore, the pharmaceutical manufacturer presented an indirect comparison without a bridge comparator between the ELARA trial and the retrospective ReCORD study.
  • For the propensity score-weighted indirect comparison, there are major uncertainties regarding the comparability of the study populations.
  • Due to limitations regarding the identification of confounders and effect modifiers, the results based on the propensity score-weighted Cox proportional hazards model are not taken into account.
  • The results of the unweighted Cox proportional-hazards model do not indicate any effects of a magnitude such that it can be assumed with sufficient certainty that the observed differences are not due solely to systematic bias; consequently, these results are also disregarded.
  • With regard to the ELARA study, the pharmaceutical manufacturer has provided data on mortality, morbidity, quality of life and side effects. The data collected on patient-reported endpoints in the categories of morbidity and quality of life are not usable. Notwithstanding this, a comparative assessment across all endpoint categories is not possible due to the single-arm study design.
  • Overall, the extent of the additional benefit is classified as non-quantifiable, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.