Trastuzumab deruxtecan (2) – Enhertu®

• Clinical trials
  • To demonstrate the additional benefit of trastuzumab deruxtecan compared with treatment as clinically indicated, the pharmaceutical manufacturer has submitted results from the ongoing, open-label, randomised and controlled, two-arm Phase III trial DESTINY-Breast02.

Adult patients with HER2-positive unresectable or metastatic breast cancer who have previously been treated with two or more anti-HER2-based therapies

• On balance, the G-BA concludes that, particularly given the extent of the prolongation in survival and in view of the positive effects on morbidity and quality of life, trastuzumab-deruxtecan in the treatment of adult patients with inoperable or metastatic HER2-positive breast cancer who have already received at least two prior anti-HER2 therapies, there is a considerable additional benefit compared with treatment as clinically indicated.
• Consequently, the G-BA concludes that trastuzumab deruxtecan demonstrates an indication of considerable additional benefit compared with the appropriate comparator therapy.
• mortality
  • In the DESTINY-Breast02 trial, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of trastuzumab deruxtecan compared with standard of care.
  • The resulting prolongation of survival achieved through treatment with trastuzumab deruxtecan is regarded as a significant improvement.
  • When evaluating the data on overall survival, it should be borne in mind that a high proportion of patients were censored within the first year.
  • It is assumed that the reasons for most early censoring are withdrawal of consent or loss to follow-up, as the study has been running for at least 1.5 years since the inclusion of the last patient and censoring due to the data cut-off is only to be expected at a later stage.
  • Furthermore, there is a significant difference in the proportions of censoring due to withdrawal of consent or loss to follow-up between the treatment arms, in that this proportion is considerably higher in the control group than in the intervention group.
  • Furthermore, approximately 30% of patients in the control arm received trastuzumab deruxtecan as a subsequent antineoplastic therapy, in the sense of a treatment switch.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the DESTINY-Breast02 trial.
  • PFS was defined as the time from randomisation to the earliest date of the first objective documentation of radiological tumour progression according to RECIST version 1.1 or the patient’s death, regardless of the cause of death – whichever event occurred first.
  • There is a statistically significant difference between the treatment arms in favour of trastuzumab deruxtecan.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• Health-related quality of life (assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23)
  • Health-related quality of life was assessed in the DESTINY-Breast02 study using the functional scales and the global health status scale of the cancer-specific EORTC QLQ-C30 and the breast cancer-specific supplementary module EORTC QLQ-BR23 for the duration of treatment with the study medication plus 40 days, and for a further 3 months.
  • The pharmaceutical manufacturer provides analyses for the ‘time to first deterioration’ and for the ‘time to multiple confirmed deteriorations’ of ≥ 10 points or ≥ 15 points.
  • No usable data are available for the endpoint ‘enjoyment of sex’.
  • For the endpoints ‘emotional functioning’, ‘body image’, ‘sexual activity’ and ‘future outlook’, no statistically significant difference was observed between the treatment arms in any case.
  • In the overall assessment of the results, an advantage of trastuzumab deruxtecan over treatment as directed by the doctor is observed for health-related quality of life as a whole.
• Side effects (AEs), total
  • In the DESTINY-Breast02 trial, almost all randomised patients experienced at least one adverse event.
• Overall assessment
  • For the assessment of the additional benefit of trastuzumab deruxtecan in the treatment of inoperable or metastatic HER2-positive breast cancer in adult patients who have already received at least two prior HER2-targeted treatments, results are available from the randomised, controlled, open-label, DESTINY-Breast02 study, results are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects, compared with treatment as directed by the clinician.
  • In the mortality endpoint category, the overall survival endpoint shows a statistically significant prolongation of survival with trastuzumab deruxtecan compared with standard of care, which is assessed as a marked improvement.
  • In the morbidity category, an advantage for treatment with trastuzumab deruxtecan was observed for the health status endpoint, which is assessed as a significant improvement in health status.
  • With regard to symptoms, treatment with trastuzumab deruxtecan has positive effects on the endpoints of pain, insomnia, diarrhoea, chest symptoms and arm symptoms, as well as negative effects on the endpoints of ‘nausea and vomiting’ and constipation.
  • Overall, trastuzumab deruxtecan offers an advantage in terms of symptoms.
  • Trastuzumab deruxtecan also offers an advantage in terms of health-related quality of life compared with treatment as directed by the doctor.
  • An overall review of the results on side effects reveals no differences between the treatment arms that are relevant to the benefit assessment.
  • On balance, the G-BA concludes that, particularly given the extent of the prolongation in survival and in view of the positive effects on morbidity and quality of life, trastuzumab-deruxtecan offers a considerable additional benefit compared with treatment as clinically indicated in the treatment of adult patients with inoperable or metastatic HER2-positive breast cancer who have already received at least two prior HER2-targeted treatments.

Courtesy translation only, please refer to the German original.