Tremelimumab (1) – Imjudo®

• Clinical trials
  • The HIMALAYA trial is an open-label, randomised, controlled trial comparing durvalumab in combination with tremelimumab or durvalumab as monotherapy against sorafenib, with four treatment arms.
  • The IMbrave150 trial is an open-label, randomised, controlled Phase III trial conducted between 2018 and 2022 at 111 trial centres in Asia, Australia, Europe and North America.

a) Adults with advanced or unresectable hepatocellular carcinoma (HCC) with Child-Pugh A or no liver cirrhosis; first-line treatment

• An additional benefit is not proven.
• Overall, the additional benefit of tremelimumab in combination with durvalumab compared with atezolizumab in combination with bevacizumab in adults with advanced or unresectable HCC with Child-Pugh A or no liver cirrhosis is not proven.
• mortality
  • For the endpoint of overall survival, the adjusted indirect comparison shows no statistically significant difference between tremelimumab + durvalumab and atezolizumab + bevacizumab.
  • Consequently, there is no hint that suggests an additional benefit of tremelimumab plus durvalumab compared with atezolizumab plus bevacizumab; an additional benefit is therefore not proven.
• Morbidity and health-related quality of life
  • No suitable data are available for an indirect comparison of the endpoints in the categories of morbidity and quality of life.
  • Differences in the duration of follow-up are evident in both the HIMALAYA study and the IMbrave150 study.
  • Furthermore, for all the aforementioned endpoints relating to morbidity and health-related quality of life, there is a high potential for bias – at least due to the lack of blinding in the assessment of subjective endpoints – meaning that the requirement for certainty of results necessary to carry out an adjusted indirect comparison would not be met.
• Side effects
  • Total AEs
  • Adverse events occurred in almost all patients in the HIMALAYA and IMbrave150 trials.
  • Serious adverse events (SAEs)
  • For the SAE endpoint, the adjusted indirect comparison shows no statistically significant difference between tremelimumab + durvalumab and atezolizumab + bevacizumab.
  • Severe AEs (CTCAE grade ≥ 3), discontinuation due to AEs
  • Endpoints relating to side effects are recorded for the duration of treatment with the study medication. Consequently, the observation period for the aforementioned endpoints varies from patient to patient in both trials.
  • For the results of the endpoint ‘discontinuation due to AEs’, the open-label study design also leads to a high potential for bias.
  • Due to these limitations, there are uncertainties regarding the interpretation of the results for the endpoint ‘severe AEs’ from the indirect comparison.
  • For the endpoint ‘withdrawal due to AEs’, the certainty of the results is insufficient in the respective HIMALAYA and IMbrave150 studies. The requirements for an adjusted indirect comparison are therefore not met.
  • PRO-CTCAE, immune-mediated AEs and bleeding
  • The endpoints PRO-CTCAE and bleeding were recorded in the HIMALAYA and/or IMbrave150 studies, but no data on these endpoints were provided in the dossier.
  • For the endpoint ‘immune-mediated AEs’, there is no analysis of the comparability of the operationalisations of immune-mediated AEs between the studies.
  • No data, or no suitable data, are available for the endpoints PRO-CTCAE, bleeding and immune-mediated AEs.
  • Overall, there is no hint that tremelimumab + durvalumab offers any advantage or disadvantage over atezolizumab + bevacizumab in terms of side effects.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab in adults with advanced or unresectable HCC with Child-Pugh A or no liver cirrhosis, results are available from the adjusted indirect comparison of the HIMALAYA study with the IMbrave150 study, using sorafenib as the bridge comparator.
  • The studies presented are sufficiently similar and, overall, suitable for conducting an adjusted indirect comparison.
  • No difference relevant to the assessment is evident for the endpoint of overall survival.
  • No suitable data are available for the endpoint categories of morbidity and quality of life.
  • For the endpoint category ‘side effects’, no differences relevant to the assessment are evident for the endpoint ‘serious AEs’. There are uncertainties regarding the interpretation of the results for the endpoint ‘severe AEs’. No suitable data are available for the endpoint ‘discontinuation due to AEs’.

b) Adults with advanced or unresectable hepatocellular carcinoma (HCC) with Child-Pugh B; first-line treatment

• An additional benefit is not proven.
• For adults with advanced or unresectable hepatocellular carcinoma (HCC) with Child-Pugh B status receiving first-line treatment, the pharmaceutical manufacturer has not provided any data for the assessment of additional benefit. Consequently, additional benefit is not proven.

Courtesy translation only, please refer to the German original.