NeoAdjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Trastuzumab-deruxtecan Versus Pacli-/Docetaxel+Carboplatin+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer
ADAPT-HER2-IV will address question of optimal neoadjuvant therapy in patients with less advanced -HER2+ EBC. ADAPT-HER2-IV is planned as a superiority trial to demonstrate higher pCR rates in both clinically relevant subgroups of low-intermediate risk HER2+ EBC. Moreover, it aims to demonstrate excellent survival in patients treated by T-DXd (with the use of standard chemotherapy at investigator´s decision restricted only to patients with substantial residual tumour burden after T-DXd-treatment).
⁃ Patients eligible for inclusion in this study must meet all the following criteria:
⁃ 1\. Female patients with invasive, untreated HER2+ breast cancer (as assessed by local pathology) maximum 6 weeks before registration (standard-of-care diagnostic biopsy according to current AGO guidelines) 2. Age ≥18 years 3a. Cohort 1: low- to intermediate-risk for recurrence as per investigator´s decision (recommendation: cT1c - cT2 (1 - ≤3cm) AND cN0; cT1a/b, cN0 excluded), OR 3b. Cohort 2: intermediate- to high-risk for recurrence as per investigator´s decision (recommendation: cT2 (\>3 - ≤5cm), cN0) 3c. Cohort 3: intermediate- to high-risk for recurrence as per investigator´s decision, (recommendation: clinical stage II (cT2, cN0); cT1c, cN0 only if neoadjuvant treatment intended) 4. Written informed consent 5. LVEF ≥ 50% within 28 days before randomisation 6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 7. Adequate bone marrow and organ function within 14 days before randomisation as defined by the following laboratory values:
• absolute neutrophil count ≥ 1.5 × 109/L,
• platelets ≥ 100 × 109/L,
• haemoglobin ≥ 9.0 g/dL:
• estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula,
• INR ≤ 1.5,
• serum creatinine \< 1.5 mg/dL,
• total bilirubin \< ULN, except for patients with Gilbert's Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN,
• aspartate transaminase (AST) \< 2.5 × ULN,
• alanine transaminase (ALT) \< 2.5 × ULN. 8. Adequate treatment washout period before randomisation (refer to protocol for detailed information) 9. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential (refer to protocol for detailed information) Post-menopausal status is accepted for women, who at the time of initiation of study medication, either
• had underwent bilateral oophorectomy, or
• are ≥ 60 years of age, or
• are \< 60 years of age and amenorrhoeic for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression)
• and/or whose FSH- and oestradiol-blood values are within the postmenopausal range per local laboratory normal range.
• 10\. Female subjects must not donate, or retrieve for their own use, ova from the time of randomisation and throughout the study treatment period, and for at least 7 months after the final study drug administration.