Trastuzumab deruxtecan (1) – Enhertu®

• Clinical trials
  • DESTINY-Breast03 is a randomised, multicentre, open-label, controlled Phase III trial comparing trastuzumab deruxtecan with trastuzumab emtansine.

Adults with HER2-positive unresectable or metastatic breast cancer who have previously been treated with anti-HER2-based therapy

• mortality
  • In the DESTINY-Breast03 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause.
  • For the endpoint of overall survival, a statistically significant difference was observed in favour of trastuzumab deruxtecan.
  • An effect modification was observed for the characteristic ‘age’. In the subgroup analysis, a statistically significant advantage in favour of trastuzumab deruxtecan was observed for patients aged < 65 years. In contrast, no statistically significant advantage was observed for patients aged ≥ 65 years.
  • These subgroup results are regarded as a relevant finding of the present benefit assessment. However, they are not considered sufficient to differentiate by age in the overall assessment and to derive separate conclusions regarding the additional benefit accordingly.
  • However, in conjunction with the additional limitations of the DESTINY-Breast03 study regarding prior treatments, significant uncertainty remains regarding the quantification of the extent of the additional benefit for the entire study population.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the DESTINY-Breast03 study. PFS was defined as the time from randomisation to the first documented radiological tumour progression or the death of the patient, regardless of the cause of death.
  • There is a statistically significant difference between the treatment arms.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of this endpoint is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘morbidity’ component is not assessed on the basis of symptoms, but by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria, version 1.1).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected.
• Health-related quality of life
  • Health-related quality of life was assessed in the DESTINY-Breast03 study using the functional scales of the EORTC QLQ-C30 and EORTC QLQ-BR23.
  • The pharmaceutical manufacturer must provide analyses for the time to first deterioration and for the time to multiple confirmed deteriorations of ≥ 10 points or ≥ 15 points. For the EORTC questionnaires, only analyses relating to the 10-point response criterion are to be included in the dossier.
  • For the health-related quality of life endpoints, too, the analyses of time to first deterioration are used in accordance with the above remarks on symptomatology.
  • For the role functioning and cognitive functioning endpoints, statistically significant differences in favour of trastuzumab deruxtecan are observed.
  • For the ‘body image’ endpoint, a statistically significant difference was observed to the disadvantage of trastuzumab deruxtecan.
  • No statistically significant differences were observed for the other endpoints. No usable data are available for the ‘Enjoyment of Sex’ scale.
• Side effects – Total adverse events (AEs)
  • In the DESTINY-Breast03 trial, AEs occurred in almost all patients enrolled in both treatment arms. The results are presented here for supplementary information only.
• Overall assessment
  • For the benefit assessment of trastuzumab deruxtecan in the treatment of adults with HER2-positive unresectable or metastatic breast cancer who have previously received anti-HER2-based therapy, results from the DESTINY-Breast03 trial are available regarding mortality, morbidity (symptoms and health status), health-related quality of life and side effects.
  • The results for the overall survival endpoint show that treatment with trastuzumab deruxtecan leads to a prolongation of overall survival compared with trastuzumab emtansine. For this endpoint, there is an effect modification by the characteristic of age. For individuals aged < 65 years, there is a statistically significant advantage in favour of trastuzumab deruxtecan. For individuals aged ≥ 65 years, however, there is no statistically significant advantage. In conjunction with the additional limitations of the DESTINY-Breast03 study regarding prior treatments, this results in significant uncertainty regarding the quantification of the extent of the additional benefit for the entire study population.
  • In the morbidity category, there are both advantages and disadvantages for trastuzumab deruxtecan in terms of symptoms. Additional benefit is not proven for the health status endpoint (EQ-5D VAS). In the overall assessment of the results, there is no clear advantage or disadvantage of trastuzumab deruxtecan compared with trastuzumab emtansine in the morbidity endpoint category.
  • Overall, no clear advantage or disadvantage of trastuzumab deruxtecan compared with trastuzumab emtansine can be identified with regard to quality of life.
  • With regard to side effects, an advantage for trastuzumab deruxtecan is observed for the endpoints of serious adverse events and severe AEs. There is no significant difference for the endpoint of treatment discontinuation due to AEs. With regard to specific adverse events, there are both advantages and disadvantages. In summary, the endpoints relating to side effects predominantly show advantages for trastuzumab deruxtecan compared with trastuzumab emtansine.
  • Overall, advantages are evident in terms of overall survival and side effects. No relevant differences between the treatments were observed in terms of symptoms, health status or health-related quality of life. With regard to the advantage in overall survival, there is significant uncertainty regarding the quantification of the extent of the additional benefit for the entire study population due to effect modification by the characteristic of age. Furthermore, there are uncertainties regarding the prior treatments received by the patients included in the DESTINY-Breast03 trial. For these reasons, the extent of the additional benefit cannot be reliably quantified in the overall assessment.

Courtesy translation only, please refer to the German original.