Brexucabtagen-Autoleucel / Autologe Anti-CD19-transduzierte CD3+ Zellen (1) – Tecartus®, Autologe Anti-CD19-transduzierte CD3-positive Zellen

• Clinical trials
  • The ZUMA-2 trial is a single-arm Phase II trial designed to investigate the safety and efficacy of autologous anti-CD19-transduced CD3-positive cells (KTE-X19) in adult patients with relapsed or refractory mantle cell lymphoma.

Adult patients with relapsed or refractory mantle cell lymphoma (MCL) following two or more systemic therapies, including a Bruton’s tyrosine kinase (BTK) inhibitor

• In summary, the additional benefit of autologous anti-CD19-transduced CD3-positive cells is assessed as follows:
• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• The certainty of the evidence is assessed as a hint because only a single-arm study is available and a comparative assessment is not possible.
• Overall, there is a hint of a non-quantifiable additional benefit for Tecartus® because the scientific evidence does not permit quantification.
• mortality
  • In the ZUMA-2 study, the overall survival endpoint is defined as the time from administration of the study medication to death from any cause for analyses of the modified ITT (mITT) population and in the Inferential Analysis Set (IAS) or, for the Full Analysis Set (FAS) as the time from study enrolment to death.
  • At the data cut-off date of 31 December 2020, the median survival time had not yet been reached. 32 (43 %) of the patients had died by this date.
  • Due to the single-arm study design, a comparative assessment of the mortality results is not possible.
• Morbidity – Progression-Free Survival (PFS)
  • Progression-free survival is defined in this study as the time from CAR-T cell infusion to death or the onset of disease progression, as assessed by an independent radiological reviewcommittee in accordance with the Lugano criteria, as well as by assessment by the medical trial staff in accordance with the IWG response criteria.
  • At the data cut-off date of 31 December 2020, 27 (45 %) of the patients in the inferential analysis set had experienced an event.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Due to the single-arm study design, a comparative assessment is not possible.
• Morbidity – Complete Response
  • In the ZUMA-2 study, the endpoint ‘complete response’ is a sub-component of the endpoint ‘best objective response’.
  • At the data cut-off date of 31 December 2020, 46 (62%) of the patients had achieved a complete response (as assessed by the medical trial staff).
  • Due to the single-arm study design, a comparative assessment of the response or the rate of complete remissions is not possible.
• Morbidity – EQ-5D VAS
  • Health status was assessed in the ZUMA-2 study using the EuroQoL 5-Dimensional Visual Analogue Scale.
  • The pharmaceutical manufacturer has presented responder analyses based on a deterioration of 10 points. This does not correspond to a responder threshold of 15 per cent and was not pre-specified.
  • At month 3, there was a change of –2.4 compared with baseline.
  • Due to the single-arm study design, a comparative assessment is not possible.
• quality of life
  • No data on quality of life were collected in the ZUMA-2 study.
• Side effects
  • Following infusion of the autologous anti-CD19-transduced CD3-positive cells (KTE-X19), every patient had experienced at least one adverse event. 67 (99 %) of the patients experienced a severe AE of grade ≥ 3 (according to CTCAE or cytokine release syndrome as defined by Lee et al. 2014).
  • In 48 (71 %) of the patients, a serious adverse event occurred following the CAR-T infusion.
  • Severe AEs (CTCAE grade ≥ 3) with an incidence of ≥ 5% and > 1 event were most frequently observed in the SOC ‘Blood and lymphatic system disorders’.
  • AE of particular interest included cytokine release syndrome (91% of patients), neurological events (63%), cytopenias (thrombocytopenia, neutropenia, anaemia) (96%), infections (53%) and hypogammaglobulinaemia (21%).
  • Due to the single-arm study design, a comparative assessment of the results regarding side effects is not possible.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of autologous anti-CD19-transduced CD3-positive cells for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) following two or more systemic therapies including a Bruton’s tyrosine kinase(BTK) inhibitor, the results of the pivotal single-arm Phase II ZUMA-2 trial are used.
  • Neither the indirect comparison with a meta-analysis of eight external studies, as set out by the pharmaceutical manufacturer in the dossier, nor the indirect comparison with the SCHOLAR-2 study, as presented during the commenting procedure, is suitable for drawing conclusions regarding the extent of the additional benefit.
  • With regard to the meta-analysis, relevant information is lacking to enable a comparison with the ZUMA-2 study.
  • The indirect comparison between the ZUMA-2 and SCHOLAR-2 studies is subject to major uncertainties, arising in particular from the question of whether the study populations are sufficiently comparable and from the minor sample size of the SCHOLAR-2 study.
  • Taking these uncertainties into account, the comparative effect estimate is also not of a magnitude that would allow an effect to be inferred with sufficient certainty.
  • In summary, the available results are, on balance, 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.