Atezolizumab (8) – Tecentriq®

• Clinical trials
  • To demonstrate the additional benefit of atezolizumab in combination with bevacizumab compared with sorafenib, the pharmaceutical manufacturer has submitted the results of the open-label, randomised, controlled Phase III IMbrave150 trial.

a) Adult patients with advanced HCC who are Child-Pugh A or have no liver cirrhosis and have not received prior systemic therapy

• mortality
  • Overall survival in the overall population as at the data cut-off date of 31 August 2020 was statistically significantly prolonged in the atezolizumab + bevacizumab treatment group compared with the control group.
  • Treatment with atezolizumab + bevacizumab resulted in a prolongation of survival compared with treatment with sorafenib, which is considered a significant improvement.
  • Furthermore, a subgroup analysis based on the aetiology of HCC revealed an effect modification. For patients with HCC of viral aetiology, a statistically significant advantage in overall survival was observed in favour of atezolizumab + bevacizumab compared with sorafenib. In contrast, no statistically significant difference was observed for the patient population with non-viral aetiology.
  • The available subgroup results regarding the aetiology of HCC are currently considered insufficiently robust to allow for a separate assessment of additional benefit.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was one of the co-primary efficacy endpoints in the study. It was defined as the time from randomisation to the first occurrence of disease progression or death from any cause, whichever occurred first.
  • PFS was statistically significantly prolonged in the atezolizumab + bevacizumab treatment group compared with the control group.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The mortality component of this endpoint was assessed in the IMbrave150 study via the overall survival endpoint as a standalone endpoint. The morbidity component, disease progression, was assessed solely by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria). Consequently, morbidity is not primarily assessed on the basis of disease symptoms, but solely on the basis of asymptomatic findings that are not directly relevant to the patient.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life was assessed in the IMbrave150 study using the global health status and functional scales of the EORTC QLQ-C30, as well as the functional scales of the EORTC QLQ-HCC18 questionnaire.
  • The pharmaceutical manufacturer has provided responder analyses for the EORTC QLQ-C30 and –HCC18 for the time to a 10-point deterioration. This analysis is used for the benefit assessment.
  • For the global health status and the functional scales for physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning of the EORTC QLQ-C30, as well as the body image and nutrition domains of the EORTC QLQ-HCC18, a statistically significant advantage was observed in favour of atezolizumab + bevacizumab compared with sorafenib.
  • For the ‘Sexual Function’ subscale of the EORTC QLQ-HCC18, no statistically significant difference was observed between the treatment groups.
  • Overall, a significant advantage for atezolizumab + bevacizumab compared with sorafenib can be inferred in the quality of life endpoint category.
• Side effects
  • Endpoints relating to side effects were recorded for the duration of treatment with the study medication, plus 90 days for serious adverse events (SAEs) and plus 30 days for other adverse events (AEs).
  • Adverse events (AEs)
  • In the IMbrave150 trial, 98.1% of patients in the intervention arm experienced an adverse event. In the control arm, the figure was 98.3% of patients.
  • Serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs
  • No statistically significant difference was observed between the treatment groups for the endpoints SUE, severe AE and discontinuation due to AE.
  • Specific AE
  • Immune-mediated AEs and haemorrhages
  • No summary analysis of immune-mediated AEs is available; instead, only results for individual immune-mediated AEs associated with atezolizumab are provided, which are not usable for the benefit assessment. A conclusive assessment of immune-mediated AEs is therefore not possible.
  • For the endpoints relating to bleeding (adverse events, serious adverse events, severe adverse events), there is no statistically significant difference between the treatment groups in any case.
  • Hand-foot syndrome
  • For the hand-foot syndrome endpoint (severe AEs), there is a statistically significant advantage in favour of atezolizumab + bevacizumab compared with sorafenib.
  • Other specific AEs
  • For the endpoints of alopecia, diarrhoea and elevated serum bilirubin, and for the endpoints of general disorders and administration-site conditions, metabolic and nutritional disorders, and respiratory, thoracic and mediastinal disorders, a statistically significant advantage was observed in each case in favour of atezolizumab + bevacizumab compared with sorafenib. For the endpoint ‘infections and parasitic diseases’, a statistically significant difference was observed to the disadvantage of atezolizumab + bevacizumab compared with sorafenib.
  • Overall, no statistically significant difference was observed between the study arms with regard to side effects for the endpoints of serious adverse events, severe adverse events (CTCAE grade ≥ 3) and discontinuation due to adverse events. In detail, both positive and negative side effects of atezolizumab + bevacizumab were observed compared with sorafenib for specific AEs. A comprehensive analysis of immune-mediated side effects, suitable for a benefit assessment, would be required for a complete evaluation of side effects.
  • With regard to the endpoint category of side effects, there are overall neither advantages nor disadvantages for atezolizumab + bevacizumab compared with sorafenib.

b) Adult patients with advanced HCC, Child-Pugh B, who have not received prior systemic therapy

• An additional benefit is not proven.
• Consequently, additional benefit is not proven for atezolizumab in combination with bevacizumab.
• No data are available for the assessment of the additional benefit of atezolizumab plus bevacizumab compared with the appropriate comparator therapy in adult patients with advanced HCC and Child-Pugh B status who have not received prior systemic therapy.

Courtesy translation only, please refer to the German original.