A Randomized Trial of Trastuzumab Deruxtecan and Biology-Driven Selection of Neoadjuvant Treatment for HER2-positive Breast Cancer

Prior treatment

• Receipt of live, attenuated vaccine within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study drug
• Pre-treatment axillary surgery
• Administration of other experimental drugs, either concomitantly or during the past 30 days before treatment initiation
• A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
• Recent major surgery
• History of DCIS, except for patients treated exclusively with mastectomy >5 years prior to diagnosis of current breast cancer
• Patients with ER-positive breast cancer being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A which cannot be discontinued at least 7 days prior to planned treatment with ribociclib.
• Prior pneumonectomy

Other illness

• Any impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Any psychological, including substance abuse, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• Allergic reactions or hypersensitivity to the study drugs or other monoclonal antibodies
• Known presence of distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum. Synchronous contralateral breast cancer is allowed if the tumor is HER2 positive according to the definition of inclusion criterion 6.
• Other malignancy diagnosed during the past five years
• History of invasive breast cancer
• Active cardiac disease or a history of cardiac dysfunction
• Uncontrolled infection requiring systemic antibiotics, antivirals or antifungals
• History of (non-infectious) Interstitial Lung Disease (ILD) / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.)
• Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for patients who are included in the study.
• History of positive testing for HIV or known AIDS
• Acute or chronic infection with hepatitis B or C virus. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA

Lab values

• Concomitant medication(s) with a known risk to prolong the QT interval

Other

• Participation in other interventional trials
• Pregnant or breastfeeding female patients, or patients who are planning to become pregnant

• Women or men 18 years or older
• Negative serum pregnancy test for women of childbearing potential or for patients who have experienced menopause onset <12 months prior to randomisation
• Patients of childbearing potential must be willing to use one highly effective contraception or two effective forms of nonhormonal contraception.
• Participants must be able to communicate with the investigator and comply with the requirements of the study procedures
• Written informed consent must be given according to ICH/GCP, and national/local regulations
• Histologically confirmed breast cancer with an invasive component measuring > 20 mm and/or with morphologically confirmed spread to regional lymph nodes (stage cT2-cT4 with any cN, or cN1-cN3 with cT1-4). Ipsilateral multifocal and multicentric tumors are allowed if they fulfill inclusion criterion 6.
• Performance status 0 or 1 at the time of randomisation
• Known estrogen-receptor and/or progesterone receptor status, as assessed locally by IHC. The cut-off for positivity for ER/PR for this study is at least 10% of cell nuclei staining for ER or PR, respectively
• Known HER2-positive breast cancer defined as an IHC status of 3+. If IHC is 2+, a positive in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. ISH positivity is defined as a ratio of ≥ 2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies.
• Left Ventricular Ejection Fraction (LVEF) ≥ 50% within 28 days before randomization
• Adequate bone-marrow, hepatic and renal function
• Availability of tumor and blood samples as described in the protocol