Axicabtagen-Ciloleucel (3) – Yescarta®

• Clinical trials
  • The ZUMA-1 trial is a single-arm, multicentre Phase I/II trial designed to assess the efficacy and safety of Axi-Cel in people with relapsed or refractory (r/r) DLBCL (including the subtype transformed follicular lymphoma (TFL)) and primary mediastinal large B-cell lymphoma (PMBCL).
  • The SCHOLAR-1 study is an international, retrospective study comprising patient data from a total of four studies.

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

• Mortality – overall survival
  • With regard to the FAS population, the median overall survival for the entire population (patients with DLBCL, TFL and PMBCL) was 17.4 months.
  • The plateau in the Kaplan-Meier curves already observed at the 24-month data cut-off is confirmed by the update analysis at 60 months. The Kaplan-Meier estimator (KM estimator) changes only slightly between month 24 (47.7 per cent) and month 60 (40.5 per cent). By 60 months, 60 per cent of patients had died.
  • In an indirect comparison with the SCHOLAR-1 study, a statistically significant advantage in favour of Axi-Cel is evident (hazard ratio = 0.37 [0.26; 0.52], p < 0.0001). The 60-month survival rate for patients in the ZUMA-1 study is 41%, compared with 11% for patients in the SCHOLAR-1 study.
  • The median overall survival is shorter in patients with DLBCL (15.7 months) than in those with TFL (64.1 months) and PMBCL (cannot be estimated). The Kaplan-Meier estimator for overall survival declined more sharply in patients with DLBCL compared with month 24 than in patients with TFL; in patients with PMBCL, it remained constant.
  • Taking into account the comments regarding the uncertainties relating to the adjustment, the G-BA concludes that the effect is not of such a magnitude that it can be assumed with sufficient certainty that the differences are not solely due to systematic bias.
• Morbidity – Progression-free survival (PFS)
  • Progression was assessed using the IWG criteria as set out by Cheson et al. in 2007. The assessment was carried out both by medical trial staff and through central review.
  • This dossier presents the results for the PFS endpoint in relation to the FAS population, based on the data cut-off of 11 August 2018. An updated analysis based on the 60-month data cut-off is not available.
  • The median PFS was summarised by the pharmaceutical manufacturer for patients with DLBCL and TFL and was 9.0 months for these sub-entities. For patients with PMBCL, the median PFS had not been reached as at 11 August 2018.
  • For the overall population of the ZUMA-1 trial, the median PFS was 9.5 months. The CM estimates fell to around 37% by month 18. By month 24, there was no change in the CM estimate, with the probability of progression-free survival for patients remaining at 37% at this point.
  • Due to the single-arm study design, a comparative assessment of the study results regarding PFS is not possible.
• quality of life
  • Data on patients’ quality of life were not collected in the ZUMA-1 study.
• Side effects
  • In Phase II of the ZUMA-1 study, a comprehensive assessment of adverse events (AEs) was carried out up to study month 3 following infusion of Axi-Cel. For the period from study month 3 to study month 24 following infusion of Axi-Cel, only specific AEs were recorded (neurological events, haematological events, infections, autoimmune disorders and secondary malignancies).
  • 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’. PT encephalopathy was identified as a serious AE with an incidence of ≥ 5% and > 1 event.
  • With regard to AEs of particular interest for identified risks with an incidence of ≥ 5% and > 1 event, neurological events and various cytopenias were particularly evident at a CTCAE grade of ≥ 3. A CRS of severity ≥ 3 according to the CRS Grading Scale by Lee et al. was observed in > 10% of individuals with DLBCL.
  • Due to the single-arm study design, a comparative assessment of the results regarding side effects for both patient groups is not possible.
• Overall assessment
  • To assess the extent of the additional benefit of axicabtagen-ciloleucel (Axi-Cel) for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) following two or more systemic therapies, the pharmaceutical manufacturer submitted the results of the pivotal single-arm Phase I/II ZUMA-1 trial, as well as an indirect historical comparison with the retrospective SCHOLAR-1 study for the endpoint of overall survival.
  • No current data were presented regarding the indirect comparison based on PSM analyses. Therefore, these analyses are not taken into account for the present benefit assessment. In the analyses using the Cox proportional hazards model, as in the PSM analyses, there are uncertainties regarding the identification of effect modifiers and confounders and, consequently, regarding adequate adjustment.
  • With regard to the single-arm study data, the plateau in the Kaplan-Meier curves for overall survival, which had already been observed at the 24-month data cut-off, was confirmed by the update analysis of the ZUMA-1 study at 60 months. At 60 months, 40.5% of patients were still alive. The 60-month data reveal differences between patients with DLBCL, TFL and PMBCL. A longer median overall survival is observed in patients with TFL and PMBCL. Given that the ZUMA-1 study included a higher proportion of patients with TFL and PMBCL than the SCHOLAR-1 study, a bias in favour of ZUMA-1 cannot be ruled out. The effect is not of a magnitude such that it can be assumed that the differences are not solely due to systematic bias.
  • Due to the single-arm design of the ZUMA-1 study, no comparative assessment is possible for the endpoints relating to mortality, morbidity and side effects. Quality of life was not assessed in the ZUMA-1 study.
  • Overall, a non-quantifiable additional benefit is identified, as the scientific evidence does not permit quantification.

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

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Mortality – overall survival
  • With regard to the FAS population, the median overall survival for the entire population (patients with DLBCL, TFL and PMBCL) is 17.4 months.
  • The plateau in the Kaplan-Meier curves already observed at the 24-month data cut-off is confirmed by the update analysis at 60 months. The Kaplan–Meier estimator (KM estimator) changes only slightly between month 24 (47.7 per cent) and month 60 (40.5 per cent). By 60 months, 60 per cent of patients had died.
  • The median overall survival in patients with DLBCL (15.7 months) is shorter than that in patients with TFL (64.1 months) and PMBCL (cannot be estimated). The Kaplan-Meier estimator for overall survival declined more sharply in patients with DLBCL compared with month 24 than in patients with TFL; in patients with PMBCL, it remained constant.
  • For patients with PMBCL, no conclusions can be drawn based on the indirect comparison and the previous explanations due to the small number of patients.
• Morbidity – Progression-free survival (PFS)
  • This dossier presents the results for the PFS endpoint in relation to the FAS population, based on the data cut-off date of 11 August 2018. An updated analysis based on the 60-month data cut-off is not available.
  • For patients with PMBCL, the median PFS had not been reached as at 11 August 2018.
  • 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). Response was assessed on the basis of the 2007 IWG criteria.
  • In addition, the ORR was also assessed through central review. The response rate for patients with PMBCL was 78 per cent.
  • Due to the single-arm study design, it is not possible to carry out a comparative assessment of response or the rate of complete remissions for both patient groups.
• quality of life
  • Data on patients’ quality of life were not collected in the ZUMA-1 study.
• Side effects
  • In Phase II of the ZUMA-1 study, a comprehensive assessment of adverse events (AEs) was carried out up to study month 3 following infusion of Axi-Cel. For the period from study month 3 to study month 24 following infusion of Axi-Cel, only specific AEs were recorded (neurological events, haematological events, infections, autoimmune disorders and secondary malignancies).
  • 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 per cent and > 40 per cent, respectively.
  • Due to the single-arm study design, it is not possible to carry out a comparative assessment of the results regarding side effects for both patient groups.
• Overall assessment
  • For the assessment of the extent of the additional benefit of axicabtagen-ciloleucel (Axi-Cel) for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) following two or more systemic therapies, the pharmaceutical manufacturer submitted the results of the pivotal single-arm Phase I/II ZUMA-1 trial, as well as an indirect historical control comparison with the retrospective SCHOLAR-1 study for the endpoint of overall survival.
  • No current data were presented regarding the indirect comparison based on PSM analyses. Consequently, these analyses are not taken into account for the present benefit assessment. In the analyses using the Cox proportional hazards model, as in the PSM analyses, there are uncertainties regarding the identification of effect modifiers and confounders and, consequently, regarding adequate adjustment.
  • With regard to the single-arm study data, the plateau in the Kaplan-Meier curves for overall survival, which had already been observed at the 24-month data cut-off, was confirmed by the update analysis of the ZUMA-1 study at 60 months. At 60 months, 40.5% of patients were still alive. The 60-month data reveal differences between patients with DLBCL, TFL and PMBCL. Due to the minor number of patients with PMBCL, no conclusions can be drawn based on an indirect comparison.
  • Due to the single-arm design of the ZUMA-1 study, no comparative assessment is possible for the endpoints relating to mortality, morbidity and side effects. Quality of life was not assessed in the ZUMA-1 study.
  • Overall, a non-quantifiable additional benefit is identified, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.