Datopotamab deruxtecan (1) – Datroway®

a) Adults with inoperable or metastatic HR-positive and HER2-negative (IHC 0) breast cancer who have received endocrine therapy and one line of chemotherapy in the advanced stage

• The conclusion is that, for datopotamab deruxtecan compared with treatment as clinically indicated, involving a choice of capecitabine, eribulin or vinorelbin, additional benefit is not proven.
• mortality
  • Overall survival is a primary endpoint of the TROPION-Breast01 trial and is defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment arms for the endpoint of overall survival.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is a primary endpoint of the TROPION-Breast01 study. It is defined as the time from randomisation to the earliest date of the first objective documentation of radiological tumour progression (defined according to the RECIST 1.1 criteria) or the patient’s death, regardless of the underlying cause, whichever occurs first.
  • A statistically significant advantage in favour of datopotamab deruxtecan was observed for PFS.
  • 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 via the overall survival endpoint as a standalone endpoint. The morbidity component is assessed in accordance with RECIST criteria and thus predominantly by means of imaging procedures.
  • 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 (EORTC QLQ-C30 and PGI-S) and Health Status (EQ-5D VAS)
  • Symptoms were assessed in the TROPION-Breast01 study using the EORTC QLQ-C30 and PGI-S questionnaires. Health status was assessed using the EQ-5D visual analogue scale.
  • The response rates for the patient-reported endpoints submitted by the pharmaceutical manufacturer in the dossier indicate that a major proportion of patients were excluded from the analyses as early as the baseline assessment. At baseline, the proportion of evaluated questionnaires included in the analyses for the EORTC QLQ-C30, EQ-5D VAS and PGI-S questionnaires ranged from approximately 54% to 71%. Response rates continued to decline as the study progressed. Overall, due to the high proportion of missing values, the results for the patient-reported endpoints are not suitable for use in the benefit assessment.
• Quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed in the TROPION-Breast01 study using the EORTC QLQ-C30 questionnaire.
  • However, the response rates submitted by the pharmaceutical manufacturer in the dossier – as previously described in the section on symptoms and health status – that a major proportion of patients were already excluded from the analyses at the baseline assessment, and that response rates continued to decline over the course of the study. Similarly, due to the high proportion of missing values, the results presented on health-related quality of life are not suitable for use in the benefit assessment.
• Side effects – Total adverse events (AEs)
  • In the TROPION-Breast01 study, adverse events occurred in 96.8% of patients in the Datopotamab deruxtecan arm and 96.4% of patients in the comparator arm. The results are presented here for supplementary information only.
• Side effects – Serious SAEs and therapy discontinuations due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints of SAE and discontinuation due to AEs.
• Overall assessment
  • For the benefit assessment of datopotamab deruxtecan for the treatment of adults with inoperable or metastatic HR-positive and HER2-negative breast cancer who have received endocrine therapy and one line of chemotherapy in the advanced stage, results from the TROPION-Breast01 study are available for the endpoint categories of mortality and side effects, compared with treatment as clinically indicated, with a choice of capecitabine, eribulin or vinorelbine.
  • For the endpoint of overall survival, there was no statistically significant difference between the treatment arms.
  • No evaluable data are available for the endpoints relating to symptoms (assessed using the EORTC QLQ-C30 and PGI-C) or for health status (assessed using the EQ-5D VAS).
  • No evaluable data are available regarding health-related quality of life (assessed using the EORTC QLQ-C30).
  • With regard to side effects, there is a statistically significant advantage for datopotamab deruxtecan in terms of severe adverse events (CTCAE grade ≥ 3). In detail, there are both advantages and disadvantages regarding specific adverse events.
  • Limitations of the TROPION-Breast01 study relevant to the evaluation arise, on the one hand, from the fact that a significant proportion of patients had not received any prior treatment with anthracyclines or taxanes. Secondly, a significant proportion of patients had received follow-up treatment with endocrine therapies and/or CDK4/6 inhibitors. This is viewed critically, as the study only included patients whose disease had progressed whilst on endocrine therapy and for whom endocrine therapy was not an option.
  • When the available results on patient-relevant endpoints are considered as a whole, the only advantage observed relates to side effects. For the endpoint of overall survival, neither an advantage nor a disadvantage is evident. No evaluable data are available on morbidity and health-related quality of life. Data on health-related quality of life are considered particularly important in the present context of advanced palliative care.
  • Taking into account the aforementioned limitations relevant to the assessment, the G-BA has reached the conclusion, following a balanced assessment, that the present advantage in terms of side effects is not considered sufficient to establish, overall, a relevant and not merely minor improvement in the treatment-related benefit.

b) Adults with inoperable or metastatic HR-positive and HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine therapy and one line of chemotherapy in the advanced stage

• The additional benefit is not proven.
• No data are available to enable an assessment of the additional benefit. In its dossier, the pharmaceutical manufacturer presents data only for the patient population of patients with HER2-0 breast cancer who have received one line of chemotherapy in the advanced stage (patient population a)).

c) Adults with inoperable or metastatic HR-positive and HER2-low (IHC 1+ or IHC 2+/ISH-) and HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer, who have received endocrine therapy and at least two lines of chemotherapy in the advanced stage

• The additional benefit is not proven.
• No data are available to enable an assessment of the additional benefit. In its dossier, the pharmaceutical manufacturer presents data only for the patient population of patients with HER2-0 breast cancer who have received one line of chemotherapy in the advanced stage (patient population a)).

Courtesy translation only, please refer to the German original.