Eribulin (3) – Halaven®

• Clinical trials
  • Study 309 is an international, multicentre, randomised, controlled, open-label, two-arm Phase III study designed to directly compare eribulin with dacarbazine.

a) For patients for whom dacarbazine is a suitable treatment option

• Hint of considerable additional benefit.
• For the reasons stated, the probability of additional benefit is classified as a hint.
• mortality
  • overall survival
  • There is a statistically significant difference in overall survival between the treatment groups; the median survival time was 15.6 months with eribulin compared with 8.4 months with dacarbazine, representing a median survival benefit of 7.2 months with eribulin (hazard ratio: 0.51 [0.35; 0.75], p-value < 0.001).
  • With regard to overall survival, there is an indication of a modification of effect by both the characteristic of age (<65 years, ≥65 years) and the characteristic ‘number of previous treatment regimens for advanced soft tissue sarcoma’.
  • Given the severity of the disease and the advanced stage of the disease, the prolongation of survival achieved with eribulin is regarded as clinically relevant and as a considerable improvement in treatment-related benefit.
• Morbidity – Progression-free survival
  • Progression-free survival
  • Treatment with eribulin showed a statistically significant prolongation of progression-free survival (PFS) compared with dacarbazine: a median of 2.9 months versus 1.7 months (hazard ratio: 0.52 [0.35; 0.78]; p = 0.0015).
  • 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. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms
  • Symptoms were assessed in Study 309 using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • In the analysis of ‘time to symptom worsening’, eribulin showed a statistically significant advantage for the symptom of insomnia (HR: 0.52 [0.32; 0.88], p = 0.012).
  • For the other symptoms assessed – fatigue, pain, dyspnoea, loss of appetite, constipation and diarrhoea – there was no statistically significant difference.
  • The analyses of time to symptom worsening should be viewed critically, as response rates fell below 50% from the third cycle onwards.
  • For the symptom ‘pain’, there is proof of an effect modification by the characteristic of sex.
  • Although the data on the median time to event are subject to uncertainty due to the minor response rates, the hazard ratio nevertheless suggests that eribulin offers an advantage over dacarbazine in terms of the symptom ‘insomnia’.
• Morbidity – Health status
  • Health status was assessed using the VAS (visual analogue scale) in the EQ-5D questionnaire.
  • There is no statistically significant difference between the treatment groups; however, there is proof of an effect modification by both the ‘age’ and ‘geographical region’ characteristics.
  • In this assessment, no separate statement on additional benefit by age and region is provided.
  • For the health status endpoint (EQ-5D VAS), therefore, neither an advantage nor a disadvantage of eribulin can be inferred.
• Health-related quality of life
  • Health-related quality of life was assessed in Study 309 using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • Analyses of the time to deterioration in health-related quality of life revealed statistically significant differences in favour of eribulin for the physical (HR: 0.55 [0.33; 0.91]; p = 0.019) and social functioning (HR: 0.35 [0.20; 0.62]; p < 0.001) scales, statistically significant advantages in favour of eribulin were observed between the treatment groups.
  • The analyses of the time to deterioration in quality of life should be viewed with caution, as response rates fell below 50% from the third cycle onwards.
  • In summary, based on the available data on health-related quality of life, there are statistically significant differences in favour of eribulin.
• Side effects
  • Due to the differing treatment durations in the two treatment groups (median 97.5 days in the eribulin arm and 51 days in the dacarbazine arm), time-to-event analyses were used.
  • The analysis shows no statistically significant differences for the endpoints of AEs (total), serious AEs (SAEs), serious AEs of CTCAE grade 3 or 4, and therapy discontinuation due to an AE.
  • For the endpoint ‘severe AEs of CTCAE grade 3 or 4’, there is proof of an effect modification by the characteristic ‘number of previous treatment regimens’.
  • No advantages or disadvantages for eribulin can be inferred from the results on side effects.
• Overall assessment
  • For the assessment of the additional benefit of eribulin in the treatment of adult patients with unresectable liposarcoma who have received prior treatment with an anthracycline-containing regimen for advanced or metastatic tumour disease, results are available from Study 309 for the relevant subpopulation of the study regarding mortality (overall survival), morbidity, health-related quality of life and side effects from Study 309 for the relevant patient population of the study.
  • Of particular relevance to decision-making in this assessment and for this indication are the results on overall mortality, symptoms and quality of life, which demonstrate an additional benefit for eribulin compared with dacarbazine.
  • On balance, the substantial advantage in terms of prolonged survival, as well as the statistically significant results in favour of eribulin regarding time to symptom progression and health-related quality of life – whilst taking into account the absence of significant differences in side effects – are assessed as a significant improvement in treatment-related benefit that has not been achieved to date.
  • The G-BA classifies the extent of the additional benefit of eribulin compared with dacarbazine 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 the treatment of the disease.

b) For patients who are eligible for other treatment options (other than dacarbazine)

• The additional benefit is not proven.
• There are no data available for eribulin in this therapeutic indication that are suitable for a benefit assessment in comparison with other treatment options.

Courtesy translation only, please refer to the German original.