Trastuzumab Emtansin (2) – Kadcyla®

• Clinical trials
  • To demonstrate the additional benefit of trastuzumab emtansine, the pharmaceutical manufacturer has submitted the KATHERINE study. The KATHERINE study is an ongoing, open-label, controlled, randomised, parallel-group trial. The study compared trastuzumab emtansine with trastuzumab.

Adult patients with early-stage HER2-positive breast cancer who, following neoadjuvant taxane-based and HER2-targeted therapy, have residual invasive disease in the breast and/or lymph nodes

• When the results for patient-relevant endpoints are considered as a whole, a clear advantage in terms of preventing recurrence – which is particularly relevant in the current adjuvant treatment context – is offset by significant adverse effects on symptoms, quality of life and side effects.
• In its cost-benefit assessment, the G-BA has concluded that trastuzumab emtansine, compared with trastuzumab, offers little additional benefit in the adjuvant treatment of adult patients with HER2-positive early-stage breast cancer at high risk of recurrence who, following neoadjuvant taxane--based and HER2-targeted therapy, have invasive residual disease in the breast and/or lymph nodes. A minor additional benefit was found.
• mortality
  • Overall survival is defined in the KATHERINE study as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, no statistically significant difference was observed between the treatment groups (hazard ratio: 0.70 [95% confidence interval (CI): 0.47; 1.05]; p = 0.085).
  • At this data cut-off point, the overall number of events is minor: 5.7% vs. 7.5% deaths.
  • Further planned interim analyses, as well as the final analysis of overall survival from the currently ongoing study, are still pending.
  • An additional benefit of trastuzumab emtansine in terms of overall survival is therefore not proven.
• Morbidity – Recurrences (event rate)
  • A statistically significant advantage in favour of trastuzumab emtansine compared with trastuzumab was observed for the recurrence rate (relative risk [RR]: 0.59 [95% CI: 0.47; 0.74]; p < 0.001).
  • The extent of this effect is assessed as a significant improvement in treatment-related benefit.
  • At the time of the data cut-off, a recurrence had occurred in 13.2% of patients in the trastuzumab emtansine arm and in 22.5% of patients in the trastuzumab arm.
• Health-related quality of life
  • For the endpoints ‘physical functioning’ and ‘social functioning’, statistically significant disadvantages were observed in the trastuzumab emtansine arm at the end of treatment and at the 12-month follow-up.
  • The analysis at the 12-month follow-up revealed statistically significant differences for the endpoints ‘role functioning’ and ‘body image’. For the endpoint ‘role functioning’, the difference was to the disadvantage of the trastuzumab emtansine arm, whilst for the endpoint ‘body image’, it was to the advantage of the trastuzumab emtansine arm.
  • For the endpoint ‘overall health status’, no statistically significant difference was observed between the treatment arms in the overall population.
  • However, for all statistically significant 12-month follow-up analyses, the Hedges’ g values do not lie entirely outside the irrelevance range. It cannot therefore be concluded that the observed effects at the 12-month follow-up are relevant.
  • Although, based on the available results, neither an advantage nor a disadvantage can be inferred for trastuzumab emtansine at the 12-month follow-up, adverse effects on quality of life are nevertheless assumed for the treatment period.
• Side effects – Serious adverse events (SAEs)
  • For serious adverse events, there is a statistically significant difference in favor of trastuzumab emtansine compared with trastuzumab.
• Overall assessment
  • For the assessment of the additional benefit of trastuzumab emtansine, results on mortality (overall survival), morbidity, quality of life and side effects compared with the appropriate comparator therapy (trastuzumab).
  • With regard to mortality, the preliminary data for the endpoint of overall survival do not allow for a definitive assessment of the effects on overall survival. Based on the available data, there is no statistically significant difference in overall survival between the study arms. The final analyses for the overall survival endpoint are pending. An additional benefit of trastuzumab emtansine in terms of overall survival is therefore not proven.
  • With regard to disease recurrence, as represented by the recurrence rate and DFS, there were statistically significantly fewer recurrences with trastuzumab emtansine compared with trastuzumab. The extent of this effect is assessed as a marked improvement in treatment-related benefit. The prevention of relapses represents an essential therapeutic goal in the present curative treatment setting.
  • At the end of treatment and at the 12-month follow-up, there were disadvantages associated with treatment with trastuzumab emtansine in terms of symptoms. At the 12-month follow-up, it cannot be concluded that these disadvantages are clinically relevant. Nevertheless, major disadvantages for symptoms are assumed for the treatment period as a whole. For the endpoint of general health status (assessed using the EQ-5D VAS), there is no disadvantage of trastuzumab emtansine.
  • When assessing the impact of trastuzumab emtansine on quality of life, disadvantages are anticipated over the treatment period.
  • With regard to side effects, there are clear disadvantages associated with trastuzumab emtansine, as evidenced by an increase in serious adverse events, severe adverse events (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events. In detail, disadvantages are evident in the specific adverse events.
  • In the overall assessment of the results for patient-relevant endpoints, a clear advantage in the present adjuvant therapy setting – particularly the prevention of recurrence – is offset by significant negative effects on symptoms, quality of life and side effects. Taking into account the current aim of curative treatment for early-stage breast cancer, the disadvantages in terms of symptoms, quality of life and side effects are weighed against the advantage in preventing recurrence.
• Overall assessment
  • In the overall assessment of the results, a clear advantage in preventing recurrence is offset by significant adverse effects on symptoms, quality of life and side effects. The disadvantages are weighed against the background of the current aim of curative treatment.
  • In the overall assessment, there is an indication of a minor additional benefit of trastuzumab emtansine compared with trastuzumab.

Courtesy translation only, please refer to the German original.