Tucatinib (1) – Tukysa®

• Clinical trials
  • To demonstrate the additional benefit of tucatinib in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone, the pharmaceutical manufacturer has submitted results from the ongoing, double-blind, randomised and controlled HER2CLIMB trial.

Adult patients with HER2-positive, locally advanced or metastatic breast cancer who have previously received at least two HER2-targeted treatment regimens

• Consequently, the G-BA has determined that tucatinib + trastuzumab + capecitabine, for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have previously received at least two HER2-targeted treatment regimens, compared with the appropriate comparator therapy, we found a considerable additional benefit.
• mortality
  • As of the data cut-off date of 4 September 2019, overall survival was statistically significantly prolonged in the tucatinib + trastuzumab + capecitabine treatment group compared with the control group (trastuzumab + capecitabine).
  • Treatment with tucatinib + trastuzumab + capecitabine results in a prolongation of survival compared with treatment with trastuzumab + capecitabine, the extent of which is assessed as a significant improvement.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) was the primary endpoint in the HER2CLIMB 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 tucatinib + trastuzumab + capecitabine treatment group compared with the control group.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding the extent of the additional benefit remains unaffected.
• Morbidity – Health status (EQ-5D VAS)
  • In the HER2CLIMB study, health status was assessed using the EQ-5D VAS questionnaire.
  • For patients in the HER2CLIMB study, there was no statistically significant difference between the treatment groups, either for a decrease in the score of ≥ 7 points or of ≥ 10 points.
  • With regard to the health status endpoint, there is therefore neither an advantage nor a disadvantage for tucatinib in combination with trastuzumab and capecitabine.
• quality of life
  • No data on health-related quality of life were collected in the HER2CLIMB study.
• Side effects – Adverse events
  • In the HER2CLIMB study, 99.3% of patients in the intervention arm experienced an adverse event. In the control arm, the figure was 97.0% of patients.
  • The results for the endpoint ‘total adverse events’ are presented for supplementary information only.
• Side effects – SUEs, severe adverse events (CTCAE grade ≥ 3), discontinuation due to adverse events
  • For the endpoints SUEs, severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs, there was no statistically significant difference between the treatment groups in any case.
• Side effects – specific AEs
  • In detail, for specific AEs, there was an advantage in the endpoint ‘dyspnoea’ (PT, severe AEs [CTCAE grade ≥ 3]), which was offset by a disadvantage in other specific AEs.
  • Disadvantages were observed in the endpoints ‘Gastrointestinal disorders’ (System Organ Class [SOC], AEs) and the endpoint ‘diarrhoea’ (preferred term [PT], AEs) contained therein, as well as for the endpoints ‘elevated alanine aminotransferase’ (PT, severe AEs [CTCAE grade ≥ 3]) and ‘elevated aspartate aminotransferase’ (PT, severe AEs [CTCAE grade ≥ 3]).
  • In the overall assessment of the ‘side effects’ endpoint category, neither an advantage nor a disadvantage can be identified for tucatinib + trastuzumab + capecitabine compared with trastuzumab + capecitabine.
• Overall assessment
  • For the assessment of the additional benefit of tucatinib + trastuzumab + capecitabine compared with trastuzumab + capecitabine in the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have previously received at least two HER2-targeted therapy regimens, results on mortality (overall survival), morbidity (health status) and side effects are available from the ongoing, double-blind, randomised and controlled HER2CLIMB trial.
  • In the mortality endpoint category, the available results for the overall survival endpoint show a statistically significant prolongation of survival with treatment with tucatinib + trastuzumab + capecitabine compared with treatment with trastuzumab + capecitabine, which is considered to have a significant extent.
  • For the morbidity endpoint category, with regard to the health status endpoint, there were neither positive nor negative effects of treatment with tucatinib + trastuzumab + capecitabine compared with treatment with trastuzumab + capecitabine.
  • No data are available regarding health-related quality of life, as this was not assessed in the HER2CLIMB study.
  • With regard to side effects, neither an advantage nor a disadvantage can be identified for tucatinib + trastuzumab + capecitabine compared with trastuzumab + capecitabine. Statistically significant differences are observed only in specific adverse events, which indicate both advantages and disadvantages.
  • Taking the available results on patient-relevant endpoints as a whole, the advantage in overall survival is not offset by any disadvantages in terms of morbidity or side effects.

Courtesy translation only, please refer to the German original.