Zanidatamab (1) – Ziihera®

• Clinical trials
  • The HERIZON-BTC-01 trial is a multicentre, open-label, single-arm PhaseIIb trial investigating the anti-tumour activity of zanidatamab in adults with HER2-amplified, inoperable and advanced or metastatic biliary carcinoma.

Adults with inoperable, locally advanced or metastatic HER2-positive (IHC 3+) biliary carcinoma who have previously been treated with at least one systemic therapy

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• For the assessment of the extent of the additional benefit of zanidatamab in the therapeutic indication ‘Treatment of adults with inoperable, locally advanced or metastatic HER2-positive (IHC 3+) biliary tract cancer (biliary tract cancer, BTC) who have previously been treated with at least one systemic therapy”, the pharmaceutical manufacturer submitted data from the HERIZON-BTC-01 registration trial and an indirect comparison with an external comparator population.
• As this trial does not allow for a comparative assessment, no conclusion can be drawn regarding the extent of the additional benefit on the basis of the HERIZON-BTC-01 trial.
• The indirect comparison submitted, which lacks a bridge comparator, is therefore not taken into account for the present assessment.
• Overall, the comparability of the external control population and the relevant patient population of the HERIZON-BTC-01 study is not sufficiently demonstrated on the basis of the available documentation.
• Furthermore, some of the confounders that were identified and assessed as relevant were not included in the propensity score model. Moreover, the analysis is based on a sample size of only 12 individuals.
• The indirect comparison presented is assessed, on the whole, as failing to provide a data basis that is sufficiently robust to enable reliable conclusions to be drawn regarding the quantification of the additional benefit.
• On balance, the extent of the additional benefit is classified as non-quantifiable, as the scientific evidence does not permit quantification.
• The certainty of the findings regarding the established additional benefit is classified as ‘hint’.
• mortality
  • Overall survival was defined in the HERIZON-BTC-01 study as the period from the first dose of the study medication until death from any cause.
  • At the time of the data cut-off submitted for the benefit assessment, a total of 45 people (72.6%) had died. Overall survival at month 12 was 65.0%. The median survival time was 18.1 months.
  • As no comparative data are available, no conclusion can be drawn from these results regarding the extent of the additional benefit.
• Morbidity – Confirmed Objective Response Rate (cORR)
  • In the HERIZON-BTC-01 study, the cORR is a component of the tumour response endpoint and is defined as the achievement of a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria, based on the assessment of CT and/or MRI scans by an independent review committee (ICR).
  • 32 study participants (51.6%) demonstrated a cORR.
  • The cORR was assessed via independent radiological review and was therefore not symptom-based, but primarily based on imaging procedures. For this reason, this endpoint is classified as not patient-relevant.
  • As this is the primary endpoint of the HERIZON-BTC-01 study, the results are presented here for the sake of completeness.
  • Nevertheless, no conclusions regarding the extent of the additional benefit can be drawn from the results of the HERIZON-BTC-01 study for the cORR endpoint, as there is no control group.
• quality of life
  • No data on health-related quality of life were collected.
• Side effects – Total adverse events (AEs)
  • Almost all patients experienced an adverse event (98.4%). These are presented here for supplementary information only.
• Overall assessment
  • The data available for the benefit assessment of zanidatamab for the treatment of adults with inoperable, locally advanced or metastatic HER2-positive (IHC 3+) biliary carcinoma who had previously received at least one systemic therapy, data are available from the single-arm HERIZON-BTC-01 trial, on which the marketing authorisation is based, covering the categories of mortality, morbidity and side effects. As this study does not allow for a comparative assessment, no conclusion can be drawn on the extent of the additional benefit based on the HERIZON-BTC-01 study.
  • Furthermore, the pharmaceutical manufacturer has provided an indirect comparison, without a bridge comparator, between data from the relevant patient population with IHC 3+ HER2 amplification from the HERIZON-BTC-01 study and a comparison population derived from retrospective, individual patient data. On the basis of the available documentation, it cannot be assumed that, compared with the cohort from the HERIZON-BTC-01 cohort, complete and sufficiently comparable BTC-specific information was extracted for the comparison population, as a large number of the inclusion and exclusion criteria of the HERIZON-BTC-01 study could not be operationalised when selecting the comparison population. This is primarily due to the fact that relevant clinical parameters relating to treatment allocation, as well as the ECOG-PS and brain metastases, could not be taken into account, either at all or in full.
  • A further significant uncertainty lies in the fact that it cannot be ruled out that the two cohorts being compared have systematically different index time points or ‘time zeros’, and that second-line therapy was therefore initiated at different points in the course of the disease.
  • Overall, the comparability of the external control population and the relevant patient population of the HERIZON-BTC-01 study is not sufficiently demonstrated on the basis of the available documentation.
  • Furthermore, some of the confounders that were identified and assessed as relevant were not included in the propensity score model. Moreover, the analysis is based on a sample size of only 12 individuals.
  • The indirect comparison presented is assessed, on the whole, as failing to provide a data basis that is sufficiently robust to enable reliable conclusions to be drawn regarding the quantification of the additional benefit.
  • On balance, the extent of the additional benefit is classified as non-quantifiable, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.