This study will evaluate the safety and efficacy of trastuzumab deruxtecan (T-DXd) in participants with human epidermal growth factor receptor 2 (HER2)-low or HER2 immunohistochemistry (IHC) 0 (who are both hormone receptor [HR]-negative and HR-positive) unresectable and/or metastatic breast cancer.

The primary endpoint of interest in this study is time to next treatment (TTNT), a measure that will determine how long T-DXd allows patients to derive clinical benefit from the study drug.

Inclusion Criteria:

• Sign and date the main informed consent form

• Must agree to provide a newly obtained or archival baseline biopsy from primary and/or metastatic lesion.

• Pathologically documented Breast Cancer (BC) tumor

  • Is unresectable and/or metastatic.

  • Is hormone receptor-negative or hormone receptor-positive.

    • Must include percentage of positively stained cells to characterize if hormone receptor-positive or -negative.

  • Has confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC 0 status as determined according to ASCO CAP 2018 guidelines1 based on sample collected during Tissue Screening as described above.

  • Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO CAP guidelines).

  • Was never previously treated with anti-HER2 therapy in the metastatic setting.

• Has had at least one and up to two prior lines of therapy in the metastatic setting.

  • In participants with hormone receptor-positive HER2-low metastatic BC (Cohort 3):

    • Has recurrent disease <2 years from the initiation of adjuvant ET OR
    • Has disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor OR
    • Has disease progression within the first 12 months of CDK4/6 in the first line metastatic setting

• Presence of at least one measurable lesion based on computed tomography or magnetic resonance imaging.

• Participants with brain metastases are allowed in the study. The brain lesion(s) should be small (<2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and are asymptomatic and clinically stable.

• Has an Eastern Cooperative Oncology Group performance status of 0 or 1.

• Has a minimum life expectancy of 12 weeks at Screening.

• Has a left ventricular ejection fraction ≥50% within 28 days before enrollment.

• Has adequate organ and bone marrow function within 28 days before enrollment.

• Has adequate treatment washout period before enrollment.

• Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception.

Exclusion Criteria:

• Prior treatment with an antibody drug conjugate (ADC).
• Uncontrolled or significant cardiovascular disease.
• Has a corrected QT interval prolongation.
• Has a 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.
• Has spinal cord compression or clinically active central nervous system metastases.
• Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral BC.
• Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
• Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
• Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
• Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
• Has history of receiving a live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study drug.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline.
• Is pregnant or breastfeeding or planning to become pregnant.
• Lung-specific intercurrent clinically significant illnesses.
• Any autoimmune, connective tissue, or inflammatory disorders.
• Prior complete pneumonectomy.

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.