Eribulin (2) – Halaven®

• Clinical trials
  • The EMBRACE trial was conducted with a total of 762 female patients, who were randomised in a 2:1 ratio to receive treatment with eribulin (N = 508) or treatment of the investigator’s choice (Treatment of Physician’s Choice (TPC), N = 254).
  • Study 301 was an open-label, randomised, controlled trial conducted with 1,102 female patients. The patients were randomised in a 1:1 ratio to receive either eribulin (554 patients) or capecitabine (548 patients).

a) Patients who can no longer be treated with taxanes or anthracyclines

• For patients who can no longer be treated with taxanes or anthracyclines, there is a hint of considerable additional benefit.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a previously unattained significant improvement in treatment-related benefit, as a moderate prolongation of survival is achieved.
• mortality
  • The meta-analysis of the results of the two studies, 301 and EMBRACE, for this patient population shows a statistically significant prolongation of overall survival with eribulin treatment compared with treatment with capecitabine or vinorelbine (hazard ratio: 0.85, 95% CI: 0.75–0.97, p-value = 0.013).
  • For the endpoint ‘overall survival’, the meta-analysis identifies an additional benefit for eribulin compared with patient-specific chemotherapy with capecitabine or vinorelbine, the extent of which is assessed as considerable.
• Morbidity – Symptoms
  • Symptoms were assessed only in Study 301 using the symptom scales of the disease-specific EORTC QLQ-C30 questionnaire and the breast cancer-specific QLQ-BR23 supplementary module.
  • For the endpoints ‘nausea and vomiting’ and ‘diarrhoea’, a statistically significant difference in favour of eribulin was observed. However, the 95% confidence interval for Hedges’ g is not entirely below the irrelevance threshold of −0.2 in either case.
  • For the endpoint ‘side effects of systemic treatment’, there is a statistically significant difference between the treatment groups in the change from baseline, indicating a disadvantage for eribulin. The 95% confidence interval for Hedges’ g lies entirely above the non-significance threshold of 0.2.
  • For the other endpoints – ‘fatigue’, ‘pain’, ‘shortness of breath’, ‘insomnia’, ‘loss of appetite’, ‘constipation’, ‘breast symptoms’ and ‘arm symptoms’, there is no statistically significant difference between the treatment groups in the respective changes from baseline.
  • An overall review of the results from the symptom scales of the EORTC QLQ-C30 and EORTC QLQ-BR23 at the 6-week assessment point, no additional benefit of eribulin compared with the patient-specific chemotherapy regimen of capecitabine or vinorelbine was observed in terms of changes in symptoms.
• Morbidity – Pain
  • In Study 301, pain was assessed using a visual analogue scale. This endpoint is patient-relevant and is included in the assessment.
  • No data on this endpoint were submitted in the pharmaceutical manufacturer’s dossier.
• Health-related quality of life
  • Health-related quality of life was assessed only in Study 301 using the functional scales of the disease-specific EORTC QLQ-C30 questionnaire and the breast cancer-specific QLQ-BR23 supplement.
  • For the endpoint ‘sexual function’, a statistically significant difference in favour of eribulin was observed. However, the 95% confidence interval for Hedges’ g does not lie entirely below the irrelevance threshold of −0.2.
  • For the other endpoints – ‘global health status’, ‘physical functioning’, ‘role functioning’, ‘emotional functioning’, ‘cognitive functioning’, ‘social functioning’, ‘body image’, ‘sexual function’ and ‘future outlook’, no statistically significant difference was observed between the treatment groups in the changes from the respective baseline values.
  • An overall analysis of the results from the functional scales of the EORTC QLQ-C30 and EORTC QLQ-BR23 at the 6-week assessment point, no additional benefit of eribulin compared with the patient-specific chemotherapy regimen of capecitabine or vinorelbine was observed in terms of changes in health-related quality of life.
• Side effects – Adverse events
  • Due to the very high overall rate of adverse events, both in patients treated with eribulin and in those treated with capecitabine or vinorelbine, no conclusions regarding the assessment of additional benefit can be drawn from the comparative analysis at the level of this endpoint.
• Side effects – Serious adverse events (SAEs)
  • Analysis of the SAE occurring in the individual studies – EMBRACE and 301 – shows no statistically significant difference between the treatment groups. By contrast, the meta-analysis of both studies reveals a statistically significant difference, indicating an advantage or minor harm for eribulin compared with patient-specific chemotherapy with capecitabine or vinorelbine.
• Side effects – severe adverse events (CTCAE grades 3 and 4)
  • With regard to the severe adverse events (severe AEs) of CTCAE grades 3 and 4, there is a statistically significant difference between the treatment groups, indicating a disadvantage or greater harm associated with eribulin compared with patient-specific chemotherapy with capecitabine or vinorelbine.
  • In clinical practice, CTCAE Grade 3 and 4 neutropenia has direct and immediate consequences that are considered to be both clinically relevant and relevant to the patient.
• Conclusion
  • For patients who can no longer be treated with taxanes or anthracyclines, an overall assessment of the available results on mortality, morbidity, health-related quality of life and side effects, eribulin offers additional benefit compared with patient-specific chemotherapy with capecitabine or vinorelbine.
  • The G-BA classifies the extent of the additional benefit of eribulin as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
  • Classifying the extent of the additional benefit as ‘major’ is not justified, as – particularly with regard to the prolongation of survival – the extent achieved does not constitute a sustained and significant improvement in treatment-related benefit that has not previously been achieved with the appropriate comparator therapy.

b) Patients who are eligible for repeat treatment containing anthracyclines or taxanes

• For patients who are eligible for repeat treatment containing anthracyclines or taxanes, an additional benefit is not proven.
• mortality
  • With regard to overall survival, there is no statistically significant difference between the treatment groups (hazard ratio: 0.94, 95% CI: 0.69–1.29, p-value: 0.748).
  • Consequently, the additional benefit of eribulin for the endpoint ‘overall survival’ compared with re-treatment with anthracycline or taxane, as determined on an individual patient basis, is not proven.
• morbidity
  • No data are available to assess the additional benefit with regard to morbidity.
• Health-related quality of life
  • No data are available to assess the additional benefit with regard to health-related quality of life.
• Side effects – Adverse events
  • Due to the very high overall rate of adverse events in the study (EMBRACE), both in patients treated with eribulin and in those who had been re-treated with anthracyclines or taxanes, no conclusions regarding the assessment of additional benefit can be drawn from a comparative analysis of this endpoint.
• Side effects – Serious adverse events (SAEs)
  • Analysis of the SAE occurring in the EMBRACE study shows no statistically significant difference between the treatment groups.
• Side effects – Severe adverse events (CTCAE grades 3 and 4)
  • With regard to the severe adverse events (severe AEs) of CTCAE grades 3 and 4, there is a statistically significant difference indicating a disadvantage or greater harm associated with eribulin compared with re-treatment with anthracyclines or taxanes.
  • With regard to the inclusion of neutropenia in the analysis of severe AEs of CTCAE grades 3 and 4, see the relevant discussion in section a) above: ‘Patients who can no longer be treated with taxanes or anthracyclines’.
• Side effects – discontinuation due to adverse events
  • In the eribulin treatment group, fewer patients discontinued the study (EMBRACE) due to adverse events: 10.5% compared with 21.0% in the treatment group receiving re-treatment with an anthracycline or taxane. The difference is statistically significant and indicates an advantage, or minor harm, for eribulin compared with the comparator therapy for these endpoints.
• Conclusion
  • For patients eligible for re-treatment with anthracycline or taxane-based therapy, in view of the available results on mortality and side effects, there is no additional benefit of eribulin over patient-specific chemotherapy with anthracycline or taxane for any endpoint.
  • Therefore, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, an additional benefit is not proven.

c) Patients with HER2-positive breast cancer for whom anti-HER2 therapy is indicated

• For patients with HER2-positive breast cancer for whom anti-HER2 therapy is indicated, additional benefit is not proven.
• For patients with HER2-positive breast cancer, for whom anti-HER2 therapy is indicated, no data are available for a comparison of eribulin with the appropriate comparator therapy, namely anti-HER2 therapy with lapatinib in combination with capecitabine or lapatinib in combination with trastuzumab.

Courtesy translation only, please refer to the German original.