Axicabtagen-Ciloleucel (1) – Yescarta®

• Clinical trials
  • The ZUMA-1 trial is a single-arm, multicentre Phase I/II trial designed to determine the efficacy and safety of Axi-Cel in patients with chemotherapy-refractory DLBCL (including the subtype transformed follicular lymphoma (TFL)) and primary mediastinal large B-cell lymphoma (PMBCL).
  • The supportive study NCI 09-C-0082 is an open-label, single-arm Phase I dose-finding study.

a) Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) following two or more systemic therapies

• Overall, a non-quantifiable additional benefit is identified.
• Consequently, the G-BA classifies the extent of the additional benefit of axicabtagene-Ciloleucel as non-quantifiable, due to the currently limited data available, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• Mortality – Overall survival
  • With regard to the FAS population, patients with DLBCL show a median overall survival of 15.7 months, with 57 per cent of patients having died.
  • When considering the overall population, the median overall survival is 17.4 months.
  • In an indirect comparison with the SCHOLAR-1 study, there is a statistically significant advantage in favour of Axi-Cel (hazard ratio = 0.30 [0.22; 0.41], p<0.0001).
  • The 24-month survival rate for patients in the ZUMA-1 study is 50 per cent, compared with 14 per cent for patients in the SCHOLAR-1 study.
  • In view of the poor prognosis for the further course of the disease and the advanced stage of treatment, and taking into account the considerations set out above regarding the comparability of the patient populations, the G-BA assesses this effect as indicating that a benefit exists but cannot be quantified.
  • Overall, an additional benefit is identified for the endpoint of overall survival, the extent of which cannot be quantified.
• Morbidity – Progression-free survival (PFS)
  • For patients with DLBCL (Cohort 1), the median PFS in the FAS population was 7.3 months.
  • In the overall population of the ZUMA-1 study, the median PFS was 9.5 months.
  • The Kaplan-Meier estimates (KM estimates) fell to around 38% by month 18. By month 24, there was no change, or only a very slight change, in the KM estimate.
  • Due to the single-arm study design, a comparative assessment of the study results regarding PFS is not possible.
• Morbidity – Objective Response Rate (ORR)
  • The objective response rate (ORR) comprises complete and partial remission (CR and PR).
  • Due to the single-arm study design, a comparative assessment of the response or the rate of complete remissions is not possible.
• quality of life
  • Data on patients’ quality of life were not collected in the ZUMA-1 trial.
• Side effects
  • Following infusion of Axi-Cel, all patients experienced at least one AE. In particular, the rate of serious AEs (CTCAE Grade 3–4) and severe AEs rose sharply following infusion of Axi-Cel to > 90% and > 40%, respectively.
  • Severe AEs (CTCAE grade ≥ 3) with an incidence of ≥ 5% and > 1 event were most common in the SOC ‘Blood and lymphatic system disorders’.
  • CRS of severity ≥ 3 according to the CRS Grading Scale by Lee et al. was observed in > 10% of patients with DLBCL.
  • Due to the single-arm study design, a comparative assessment of the results regarding side effects is not possible.
• Overall assessment
  • The assessment of the extent of the additional benefit of axicabtagen-ciloleucel (Axi-Cel) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) following two or more systemic therapies, the results of the pivotal single-arm Phase I/II ZUMA-1 trial on mortality, morbidity and side effects are used as the basis. In addition, the mortality results from the indirect historical comparison with the retrospective SCHOLAR-1 study will be considered.
  • In an indirect comparison with the SCHOLAR-1 study, a statistically significant advantage in favour of Axi-Cel is observed for the endpoint of overall survival. In view of the poor prognosis for the further course of the disease and the advanced stage of treatment, and taking into account the considerations set out above regarding the comparability of the patient populations, the G-BA assesses this effect as indicating that an effect exists but cannot be quantified.
  • Against the background of the highly advanced stage of the disease and treatment, as well as the poor prognosis for the further course of the disease, the comparative results on overall survival are given high weighting in the overall assessment.

b) Adult patients with relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL) following two or more systemic therapies

• Overall, a non-quantifiable additional benefit is identified.
• Consequently, the G-BA classifies the extent of the additional benefit of Axicabtagen-Ciloleucel is non-quantifiable, given the currently limited data available, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• Mortality – Overall survival
  • For patients with PMBCL, the median overall survival had not yet been reached. 33% of patients had died by the time of the current data cut-off.
  • In an indirect comparison with the SCHOLAR-1 study, a statistically significant advantage in favour of Axi-Cel is evident (hazard ratio = 0.30 [0.22; 0.41], p<0.0001).
  • The 24-month survival rate for patients in the ZUMA-1 trial is 50%, compared with 14% for patients in the SCHOLAR-1 trial.
  • In view of the poor prognosis for the further course of the disease and the advanced stage of treatment, and taking into account the considerations set out above regarding the comparability of the patient populations, the G-BA assesses this effect as indicating that a benefit exists but cannot be quantified.
  • Overall, an additional benefit is identified for the endpoint of overall survival, the extent of which cannot be quantified.
• Morbidity – Progression-free survival (PFS)
  • No separate analysis of PFS is available for patients with TFL and PMBCL.
  • Due to the single-arm study design, a comparative assessment of the study results regarding PFS is not possible.
• Morbidity – Objective Response Rate (ORR)
  • The objective response rate (ORR) comprises complete and partial remission (CR and PR).
  • Due to the single-arm study design, a comparative assessment of the response or the rate of complete remissions is not possible.
• quality of life
  • Data on patients’ quality of life were not collected in the ZUMA-1 trial.
• Side effects
  • Following infusion of Axi-Cel, all patients experienced at least one AE. In particular, the rate of serious AEs (CTCAE Grade 3–4) and severe AEs rose sharply following infusion of Axi-Cel to > 90 % and > 40 %, respectively.
  • Due to the single-arm study design, a comparative assessment of the results regarding side effects is not possible.
• Overall assessment
  • The assessment of the extent of the additional benefit of axicabtagen-ciloleucel (Axi-Cel) for the treatment of adult patients with relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL) following two or more systemic therapies, the results of the pivotal single-arm Phase I/II ZUMA-1 trial on mortality, morbidity and side effects are used as the basis. In addition, the mortality results from the indirect historical control with the retrospective SCHOLAR-1 study will be used.
  • In an indirect comparison with the SCHOLAR-1 study, a statistically significant advantage in favour of Axi-Cel is observed for the endpoint of overall survival. In view of the poor prognosis for the further course of the disease and the advanced stage of treatment, and taking into account the considerations set out above regarding the comparability of the patient populations, the G-BA assesses this effect as indicating that an effect exists but cannot be quantified.
  • Against the background of the highly advanced stage of the disease and treatment, as well as the poor prognosis for the further course of the disease, the comparative results on overall survival are given high weighting in the overall assessment.

Courtesy translation only, please refer to the German original.