Neoadjuvant Trastuzumab, Pertuzumab and Zongertinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-5 Study (TRAIN-5)

Inclusion Criteria:

1. Signed written informed consent

2. Pathologically confirmed primary invasive breast cancer

3. Stage II - IIIA primary breast cancer according to TNM-staging (8th edition, AJCC); (largest tumour diameter DCE-MRI > 2cm (cT2-3) and/or cN1-2 confirmed with FNA or histology)

4. Homogeneous HER2 overexpression (IHC 3+) on pre-treatment biopsy, with confirmatory HER2 amplification by in situ hybridization

5. Known oestrogen- and progesterone-receptor expression of the invasive tumour

   a. Hormone receptor negativity is defined as expression of both oestrogen and progesterone receptors being less than 10%

6. WHO performance status of 0 or 1

7. 18 years of age or older

8. LVEF ≥50% measured by echocardiography or MUGA

9. Eligible for neoadjuvant treatment

10. Laboratory requirements within 4 weeks prior to the start of study treatment:

    1. Adequate bone marrow function (ANC ≥1.5 x 109/l, platelets ≥100 x 109/l, haemoglobin ≥5.6 mmol/L (≥90 g/L); without the use of hematopoietic growth factors within 4 weeks prior to start of trial medication.
    2. Adequate hepatic function (ALT and AST ≤3 times upper limit of normal (ULN), Alkaline phosphatase <5 times ULN, Total bilirubin ≤1.5 times the ULN, except for patients with Gilbert's syndrome: total bilirubin ≤3 times ULN or direct bilirubin ≤1.5 times ULN);
    3. Adequate renal function: Estimated Glomerular Filtration Rate (eGFR) ≥30 mL/min/1.73m2 calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula.
    4. Either International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times ULN unless on a stable dose of an anticoagulant with no unexplained elevation of INR
    5. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 times ULN unless on a stable dose of an anticoagulant with no unexplained elevation of INR

11. Women of childbearing potential (WOCBP) must be ready and able to use dual highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly during study treatment and 7 months after last dose of trastuzumab

Exclusion Criteria:

1. Inflammatory breast cancer, cT4 and/or cN3 tumours

2. Occult breast cancer (cT0)

3. Bilateral breast cancer

4. Current pregnancy or breastfeeding. Women who are breastfeeding can be enrolled if they stop breastfeeding.

5. Current or previous other malignancy unless treated without systemic therapy and more than five years ago

6. HER2 heterogeneity on pre-treatment biopsy

7. Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

8. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction, stroke, or pulmonary embolism within 6 months prior to registration.

9. Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting electrocardiograms

10. Mean resting corrected QT interval (QTcF) >470 msec (females) or >450 msec (males) based on screening 12-lead ECG

11. Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy (according to local / institutional standard) who have not been treated with suppressive antiviral therapy prior to initiation of study treatment

12. Patients with a history of HCV infection who meet one or both of the following criteria:

    1. Currently receiving curative antiviral treatment
    2. HCV viral load is above the limit of quantification (HCV RNA positive)

13. Patients with history of HIV infection who meet one or more of the following criteria;

    1. CD4+ count <350 cells/μL
    2. Viral load >400 copies/μL (local lab assessment)
    3. Not receiving antiretroviral therapy
    4. Receiving established antiretroviral therapy for less than 4 weeks prior to the start of trial treatment
    5. History of AIDS-defining opportunistic infections within 12 months prior to start of trial treatment

14. Active or known or history of non-infectious interstitial lung disease/pneumonitis

15. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g., nausea, vomiting, Crohn's disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator

16. Active infectious disease requiring systemic therapy, which puts the patient at increased risk in the opinion of the investigator.

17. Patients with severe hepatic impairment (classified as Child-Pugh C or score 10-15)

18. Known history of allergy to the trial drug(s) or any excipients of the trial drug(s) or contraindication to any of the trial drugs

19. Contraindications for MRI or or non-evaluable MRI