Trastuzumab Emtansin (1) – Kadcyla®

• Clinical trials
  • The G-BA’s assessment is based on the data from the pivotal EMILIA trial submitted by the pharmaceutical manufacturer in the dossier demonstrating additional benefit. For this randomised, open-label, controlled, international, multicentre Phase III clinical trial with a parallel-group design, the study protocol and the study reports for two evaluation time points were available.

a) Patients with HER2-positive, inoperable, locally advanced breast cancer

• For patients in patient population a, additional benefit compared with the appropriate comparator therapy is deemed not proven.
• Reason: The required evidence has not been provided (Section 35a(1), fifth sentence, of Book V of the Social Code [SGB V]).

b) Patients with HER2-positive, metastatic breast cancer, following prior treatment containing anthracyclines, taxanes and trastuzumab

• morbidity
  • Progression-free survival (PFS) was the second co-primary endpoint of the study. At the first data cut-off, the time of the final confirmatory analysis, the median PFS was 9.0 months in the trastuzumab emtansine arm versus 6.9 months in the control arm receiving lapatinib plus capecitabine (HR = 0.69; 95% CI [0.55; 0.85]; p < 0.001), corresponding to a difference of 2.1 months.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the co-primary endpoint ‘overall survival’. Furthermore, the morbidity component ‘disease progression’ in PFS was not assessed on the basis of symptoms, but exclusively by means of imaging procedures. Taking the aforementioned aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
• Health-related quality of life – time to deterioration of the physical/functional component (TOI-PFB) of the FACT-B
  • Treatment with trastuzumab emtansine resulted in a statistically significant prolongation of the median time to deterioration in health-related quality of life compared with lapatinib plus capecitabine (6.6 months versus 5.5 months). The difference between the intervention group and the control group was 1.1 months (HR: 0.80; 95% CI [0.65; 0.999]; p = 0.0495).
  • Subgroup analyses revealed an effect modification for the characteristic of ethnicity: treatment with trastuzumab emtansine resulted in a statistically significant advantage over the appropriate comparator therapy only in Caucasian patients (8.3 months versus 4.5 months). The difference between the intervention group and the control group was 3.8 months (HR: 0.66; 95% CI [0.51; 0.86]; p = 0.002).
  • The positive effects demonstrated in the dossier were limited exclusively to the physical/functional component of health-related quality of life, as this is the only component included in the TOI-PFB subscale of the FACT-B. No analyses were presented on the effect of trastuzumab emtansine on the psychosocial component or the total score of the FACT-B. However, the assessment of the TOI-PFB was pre-specified in the study protocol and the results are clinically relevant.
  • When evaluating the results on health-related quality of life, the high potential for bias—arising in particular from the lack of blinding in the EMILIA trial—must be taken into account.
• Side effects – serious adverse events
  • For the endpoint of serious adverse events (SAEs), no statistically significant difference was observed between the treatment groups. Approximately 19% of all patients experienced SAEs.
• Conclusion
  • The G-BA classifies the extent of the additional benefit of trastuzumab emtansine for patients in the patient population b, based on an overall review of the effects on patient-relevant endpoints, taking into account the severity of the disease and the therapeutic goal in the treatment of the disease, as “considerable”. Compared with the appropriate comparator therapy, a combination of lapatinib and capecitabine, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit not previously achieved, as the data from the Phase III EMILIA trial submitted by the pharmaceutical manufacturer for the benefit assessment indicate a moderate prolongation of survival (overall survival) and a significant reduction in relevant side effects.
  • The probability of the additional benefit is classified as an ‘indication’. In this assessment, account is taken, on the one hand, of the minor potential for bias regarding the overall survival endpoint, but, on the other hand, also of the potential for bias regarding the side effect endpoint, as well as the fact that only one study suitable for the benefit assessment is available.
  • Classifying the additional benefit of trastuzumab emtansine as ‘major’ is not justified, as the extent of the impact on the endpoint of overall mortality does not reach a level corresponds to the therapeutic significance of a sustained or major prolongation of survival compared with the appropriate comparator therapy, particularly given the survival time already achievable to date with established treatment options from the time of diagnosis. A sustained and previously unattained major improvement in treatment-related benefit – in particular, a cure of the disease, a major prolongation of survival, long-term freedom from severe symptoms or the largely successful avoidance of serious side effects – is not achieved.
  • For trastuzumab emtansine, the overall assessment of the ‘side effects’ endpoint, in terms of evaluating additional benefit, reveals a more favourable risk profile compared with the appropriate comparator therapy. The largely successful avoidance of severe diarrhoea and severe hand-foot syndrome is offset by an increased number of mostly mild bleeding events. In addition, trastuzumab emtansine is characterised by a positive impact on health-related quality of life (time to deterioration). However, this effect was only observed in Caucasian female patients. Morbidity data were not collected in the EMILIA trial; the impact of trastuzumab emtansine on patient-relevant disease-related symptoms, such as pain or shortness of breath, therefore remains unclear. However, particularly when deciding on palliative therapy, the impact on disease symptoms is relevant to patients, alongside prolongation of survival, health-related quality of life and side effects.

c) Patients with HER2-positive, metastatic breast cancer who have previously received treatment with taxanes and trastuzumab, but not anthracyclines

• For patients in patient population c, additional benefit compared with the appropriate comparator therapy is deemed not proven.
• Reason: The necessary evidence has not been provided (Section 35a(1), fifth sentence, of Book V of the Social Code).

Courtesy translation only, please refer to the German original.