Trial of Trastuzumab Deruxtecan in Previously Treated HER2

The purpose of this study is to test the good and bad effects of a drug called trastuzumab deruxtecan (T-DXd) in adult patients with metastatic HER2-negative breast cancer and which patients might benefit the most from T-DXd.

Inclusion Criteria: 1. Must be competent and able to comprehend, sign, and date an Institutional Review Board (IRB) approved ICF before performance of any study-specific procedures or tests. 2. Men or women ≥18 years old. 3. Pathologically documented breast cancer that is unresectable or metastatic. 4. 4.Tumor biopsies have always shown HER2-IHC 0 (\450 ms (male) based on average of Screening 12 lead ECG. 2. Uncontrolled or significant respiratory disease criteria, including any of the following: 1. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. 2. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. severe asthma, severe chronic obstructive pulmonary disorder, restrictive lung disease, symptomatic, recurrent and uncontrolled pleural effusion etc.) 3. Any autoimmune, connective tissue or inflammatory disorders, including Rheumatoid arthritis, Sjogren's, and sarcoidosis, 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 participants who are included in the study. 4. Prior pneumonectomy (complete) 3. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids to control associated symptoms. 1. Subjects with clinically inactive brain metastases may be included in the study. 2. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrolment. 4. Has history of another primary malignancy, except for: 1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence. 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3. Adequately treated carcinoma in situ without evidence of disease. 5. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product, or history of severe hypersensitivity reactions to monoclonal antibodies. 6. Has an uncontrolled infection requiring ongoing IV antibiotics, IV antivirals, or IV antifungals. 7. Has known history of human immunodeficiency virus (HIV) infection with detectable viral load or CD4 count \< 200 cells per cubic millimeter or active hepatitis B ( HBsAg positive) or C (HCV positive RNA) infection. 8. Substance abuse, medical conditions such as clinically significant cardiac or pulmonary diseases or psychological, social, familial, or geographical conditions, that would, in the opinion of the Investigators, increase the safety risk to the subject or interfere with the subject's participation in the clinical study or evaluation of the clinical study results. 9. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator \[e.g., Grade 2 chemotherapy-induced neuropathy, fatigue, residual endocrinopathies from use of immunotherapy such as hypothyroidism/hyperthyroidism, type 1 diabetes, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo)\]. 10. Is pregnant or breastfeeding, or planning to become pregnant. 11. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention. 12. Otherwise considered inappropriate for the study by the Investigator.