Axicabtagen-Ciloleucel (7) – Yescarta®

• Clinical trials
  • In the ongoing, open-label Phase III ZUMA-7 trial, axicabtagen-ciloleucel is being compared with induction therapy using R-ICE, R-DHAP, R-ESHAP and R-GDP, followed by high-dose chemotherapy (HDCT) with autologous stem cell transplantation (SCT).

a) Adults with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL), who are eligible for high-dose therapy and who relapse or are refractory to first-line therapy within 12 months of its completion

• Hint of a minor additional benefit.
• Taking into account the overall picture of the existing limitations, the certainty of the evidence for the identified additional benefit is classified as ‘hint’.
• mortality
  • In the ZUMA-7 study, overall survival was defined as the time from randomisation to death from any cause.
  • The overall survival endpoint is used for the present benefit assessment. This reveals a statistically significant advantage in favour of axicabtagen-ciloleucel. The extent of the prolongation in survival time is assessed as a minor improvement.
• Morbidity – Failure of the curative treatment approach
  • Patients in the present therapeutic indication are treated with a curative therapeutic approach. The failure of a curative therapeutic approach is, in principle, relevant to patients.
  • The event-free survival (EFS) endpoint can be used as an approximation to illustrate the failure of the curative treatment approach.
  • Consequently, despite existing uncertainties, the combined analysis of the mEFS1 and mEFS2 assessments is considered sufficiently appropriate to draw conclusions regarding the failure of the curative treatment approach; these assessments therefore form the basis of the evaluation. On this basis, an advantage of axicabtagen-ciloleucel over induction + HDCT + autologous SCT is identified, the extent of which is assessed as a minor improvement.
• quality of life
  • Quality of life was assessed in the ZUMA-7 study using the functional scales of the EORTC-QLQ-C30 questionnaire.
  • Reference is made to the above comments on the ‘symptoms’ endpoint. The results on health-related quality of life are not used for the benefit assessment.
• Side effects
  • In the ZUMA-7 study, adverse events (AEs) were recorded up to study day 150 or until a switch to another lymphoma treatment, whichever occurred first.
  • The dossier presented analyses of all endpoints relating to AEs (including time-to-event analyses) were presented for a modified safety analysis set, which comprises all patients in the intervention arm from the time of leukapheresis onwards and, in the control arm, all those who received at least one dose of induction chemotherapy.
  • serious adverse events (SAEs) and severe adverse events No statistically significant difference was observed between the study arms for the overall rates of SAEs and severe AEs.
  • Discontinuation due to AEs No data on the effect estimator are available for the endpoint ‘discontinuation due toAEs ’. However, very few events occurred in either study arm, so a statistically significant difference between the study arms can be ruled out.
  • With regard to specific AEs, a statistically significant benefit of Axicab was observed for the endpoints of febrile neutropenia (SAE), Thrombocytopenia and gastrointestinal disorders (all severe AEs), disorders of the ear and labyrinth, mucosal inflammation and hiccups.
  • For the specific AE ‘general disorders and administration site conditions’, neutropenia, psychiatric disorders and hypotension (all serious AEs), severe neurological toxicity, cough and hypoxia, axicabtagen-ciloleucel showed a statistically significant disadvantage.
  • For the endpoint ‘severe infections’, there is no statistically significant difference between the treatment arms.
  • In the overall assessment of the results, with regard to side effects, there is neither an advantage nor a disadvantage for treatment with axicabtagen-ciloleucel compared with induction chemotherapy with R-GDP, R-ICE or R-DHAP followed by high-dose therapy with autologous haematopoietic stem cell transplantation.
• Overall assessment
  • Data from the open-label, randomised Phase III ZUMA-7 trial for benefit assessment on mortality, morbidity, quality of life and side effects compared with induction therapy with R-GDP, R-ICE or R-DHAP followed by high-dose therapy with autologous stem cell transplantation.
  • A statistically significant difference in favour of axicabtagen-ciloleucel is observed for overall survival. The extent of the prolongation in survival time is assessed as a minor improvement.
  • As patients in this therapeutic indication are treated with a curative therapeutic approach, the failure of such an approach is, in principle, clinically relevant to patients. The event-free survival (EFS) endpoint is used to assess the failure of the curative therapeutic approach. In this regard, the assessment is based on the post-hoc defined analyses of EFS (mEFS1 and mEFS2). Based on these results, an advantage for axicabtagen-ciloleucel is identified, the extent of which is assessed as a minor improvement.
  • With regard to symptoms (assessed using the EORTC-QLQ-C30) and health status (assessed using the EQ-5D-VAS), no suitable data are available due to an excessively high proportion of missing values and the high proportion of patients missing from the analysis. This also applies to the data on health-related quality of life (assessed using the EORTC-QLQ-C30).
  • With regard to side effects, there are no statistically significant differences for serious side effects, severe side effects or the endpoint of discontinuation due to side effects. In detail, both advantages and disadvantages of axicabtagen-ciloleucel are evident for specific side effects.
  • In the overall assessment, therefore, for axicabtagen-ciloleucel in the treatment of DLBCL and HGBL that recurs or is refractory to first-line chemoimmunotherapy within 12 months of its completion, in patients eligible for high-dose therapy, a minor additional benefit compared with induction chemotherapy using R-GDP, R-ICE or R-DHAP followed by high-dose therapy with autologous stem cell transplantation.

Courtesy translation only, please refer to the German original.