Trastuzumab deruxtecan (6) – Enhertu®

• Clinical trials
  • The DESTINY-Breast06 trial is an ongoing, multicentre, open-label, randomised, controlled Phase III trial comparing trastuzumab deruxtecan with chemotherapy as clinically indicated, with a choice of capecitabine, paclitaxel or nab-paclitaxel, each as monotherapies.

Adults with inoperable or metastatic, hormone receptor (HR)-positive, HER2-low or HER2-ultralow breast cancer, who have received at least one course of endocrine therapy in the metastatic setting and who are not eligible for endocrine therapy as the next line of treatment

• Hint for a minor additional benefit
• Overall, there is a hint of a minor additional benefit of trastuzumab deruxtecan compared with the appropriate comparator therapy.
• mortality
  • In the DESTINY-Breast06 trial, overall survival is defined as the time from randomisation to death from any cause.
  • A statistically significant difference was observed between the treatment arms, with an advantage for trastuzumab deruxtecan; the extent of this advantage is assessed as a relevant improvement, though not exceeding a minor extent.
  • In the subgroup analysis, an effect modification was observed for the characteristic ‘age’. For patients aged < 65 years, a statistically significant advantage was observed in favour of trastuzumab deruxtecan, whilst for patients aged ≥ 65 years, no statistically significant difference was observed between the treatment groups.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the DESTINY-Breast06 trial. It is defined as the time from randomisation to the first RECIST 1.1-defined radiological disease progression or to death from any cause without prior progression, regardless of whether the patient discontinued treatment or received another antineoplastic therapy prior to progression.
  • A statistically significant advantage in favour of trastuzumab deruxtecan was observed for PFS.
• Morbidity – Symptoms (EORTC QLQ-C30, EORTC QLQ-BR45 and PGIS)
  • Symptoms were assessed in the DESTINY-Breast06 trial using the EORTC QLQ-C30, EORTC QLQ-BR45 and PGIS questionnaires.
  • As questionnaire response rates were low in both study arms from the outset, and given the further decline and variation in response rates over the course of the study, the data are generally unsuitable.
• Morbidity – Health status (EQ-5D, Visual Analogue Scale)
  • No suitable data are available for health status, as assessed using the EQ-5D VAS.
  • The questionnaire response rate was low in both study arms right from the start of the study. Due to the response rates continuing to decline and differing over the course of the study, the data are generally unsuitable.
• Morbidity – Health status (PGIC)
  • Health status was assessed using the PGIC questionnaire.
  • A statistically significant advantage was observed between the treatment arms in favour of trastuzumab deruxtecan.
  • In the morbidity endpoint category, an overall advantage was observed due to the statistically significant difference in the PGIC endpoint, which indicates a marked improvement in health status.
• Health-related quality of life (EORTC QLQ-C30 and EORTC QLQ-BR45)
  • Health-related quality of life was assessed in the DESTINY-Breast06 study using the EORTC QLQ-C30 and EORTC QLQ-BR45 questionnaires.
  • As the response rates for the questionnaires were low in both study arms right from the start of the study, and given the further decline and variation in response rates over the course of the study, the data are generally unsuitable.
  • No suitable data are available for assessing health-related quality of life.
• Side effects – Total adverse events (AEs)
  • In the DESTINY-Breast06 study, AEs occurred in almost all patients in the trastuzumab deruxtecan arm and in 95% of patients in the control arm. The results are presented here for supplementary information only.
• Side effects – serious AEs (SAEs), severe AEs and therapy discontinuations due to AEs
  • No statistically significant differences were observed between the treatment groups for the endpoints SAE, severe AEs and discontinuation due to AEs.
• Side effects – Specific AEs
  • For the endpoints musculoskeletal, connective tissue and bone disorders, nervous system disorders, hand-foot syndrome and peripheral oedema, there was a statistically significant advantage in favour of trastuzumab deruxtecan in each case.
  • A statistically significant disadvantage for trastuzumab deruxtecan was observed for the endpoints ‘reduced platelet count’, ‘investigations’, ‘anaemia’, ILD/pneumonitis, respiratory, thoracic and mediastinal disorders, reduced appetite, constipation, nausea, vomiting and alopecia.
  • Overall, no advantage or disadvantage was identified in the category of side effects.
• Overall assessment
  • For the assessment of the additional benefit of trastuzumab deruxtecan in the treatment of adults with inoperable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer, who have received at least one course of endocrine therapy in the metastatic setting and who are not eligible for endocrine therapy as the next line of treatment, results are available on mortality, morbidity, health-related quality of life and side effects from the DESTINY-Breast06 trial.
  • For overall survival, there is a statistically significant advantage favouring trastuzumab deruxtecan, whose extent is assessed as a relevant improvement, though not exceeding a minor extent.
  • In the morbidity endpoint category, no suitable data are available for symptoms, as assessed using the EORTC QLQ-C30, EORTC QLQ-BR45 and PGIS, or for health status as assessed using the EQ-5D VAS. An advantage was identified for health status, as assessed using the PGIC. Overall, an advantage for trastuzumab deruxtecan is inferred.
  • No suitable data are available regarding health-related quality of life (EORTC QLQ-C30 and -BR45).
  • For the endpoints SAE, severe AEs and therapy discontinuations due to AEs, no differences were observed between the treatment groups. In detail, advantages and disadvantages were observed for specific AEs. In the category of side effects, no overall advantage or disadvantage was identified.
  • On balance, the advantages in terms of overall survival and morbidity are not offset by any disadvantages. The G-BA concludes that, on balance, trastuzumab deruxtecan is indicated for the treatment of adults with inoperable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer, who have received at least one course of endocrine therapy in the metastatic setting and who are not eligible for endocrine therapy as the next line of treatment, offers a minor additional benefit.

Courtesy translation only, please refer to the German original.