Axicabtagen-Ciloleucel (2) – 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.
• 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
  • In the FAS population, patients with DLBCL had 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. The Kaplan-Meier estimator (KM estimator) changes only slightly between month 18 and month 24. At month 24, 47.7% of patients were still alive.
  • 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%, compared with 14% for patients in the SCHOLAR-1 study.
  • Consequently, due on the one hand to the inherently high potential for bias in an indirect historical control and, on the other hand, to additional uncertainties regarding the comparability of the patient populations, the small sample sizes, a possible selection bias arising from the selection of the analysable population in the SCHOLAR-1 study, and the historicallytime differences in data collection between the SCHOLAR-1 study and the ZUMA-1 study, it is not possible to validly quantify the extent of the additional benefit for the endpoint of overall survival.
  • 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. At month 24, there was no change, or only a very slight change, in the KM estimate. The probability of patients remaining progression-free at this point in time remained at 38 per cent.
  • 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 rates 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
  • In an indirect comparison with the SCHOLAR-1 study, a statistically significant advantage in favour of Axi-Cel is evident 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 such that an effect is present but cannot be quantified.
  • Overall, an additional benefit is identified for the endpoint of overall survival, the extent of which is non-quantifiable.
  • Due to the single-arm study design of the ZUMA-1 trial, no comparative assessment is possible for the other endpoints relating to morbidity and side effects. Patients’ quality of life was not assessed in the ZUMA-1 trial.
  • Given the 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.
  • Consequently, the G-BA assesses 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.

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

• On balance, a non-quantifiable additional benefit is identified.
• 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 study is 50%, compared with 14% for patients in the SCHOLAR-1 study.
  • Consequently, due on the one hand to the inherently high potential for bias in an indirect historical control and, on the other hand, to additional uncertainties regarding the comparability of the patient populations, the small sample sizes, a possible selection bias arising from the selection of the analysable population in the SCHOLAR-1 study and the historicallytime differences in data collection between the SCHOLAR-1 study and the ZUMA-1 study, it is not possible to validly quantify the extent of the additional benefit for the endpoint of overall survival.
  • Overall, an additional benefit is identified for the endpoint of overall survival, the extent of which cannot be quantified.
• Morbidity – Objective Response Rate (ORR)
  • 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 study.
• Side effects
  • Following infusion of Axi-Cel, all patients experienced at least one AE. In particular, the rates 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
  • In an indirect comparison with the SCHOLAR-1 study, there is a statistically significant advantage in favour of Axi-Cel 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 a benefit exists but cannot be quantified.
  • Overall, an additional benefit is identified for the endpoint of overall survival, the extent of which is non-quantifiable.
  • Due to the single-arm study design of the ZUMA-1 trial, no comparative assessment is possible for the other endpoints relating to morbidity and side effects. Patients’ quality of life was not assessed in the ZUMA-1 trial.
  • Given the 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.
  • Consequently, the G-BA assesses 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 condition.

Courtesy translation only, please refer to the German original.