This is a multi-site prospective single-arm open-label phase 2 clinical trial including 20 participants with metastatic TNBC and active brain metastases to be treated with sacituzumab tirumotecan 4 mg/kg IV on Days 1, and 15 of every 28-day cycle until disease progression, unacceptable toxicities, consent withdrawal, or death.

Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age, sex or race in the clinical trial outlined. This trial is open to the accrual of men and women.

Inclusion Criteria:

1. An individual of any sex/gender who is at least 18 years of age at the time of providing the informed consent.

2. Individuals who are unable to provide informed consent may be included if a Legally Authorized Representative (LAR) is available and able to provide consent on their behalf.

3. Histologically and/or cytologically confirmed metastatic triple-negative breast cancer defined by estrogen receptor (ER) expression <10%, progesterone receptor expression <10% and HER2-negative status, defined by 0, 1+ or 2+ FISH negative by immunohistochemistry (IHC) by standard pathology.

4. Newly diagnosed untreated brain metastases or brain metastases progressing after prior local therapy (including surgery and/or radiation therapy).

5. Intracranial measurable disease (RANO-BM criteria).

   1. Measurable disease is defined as a contrast enhancing lesion that is at least 10 mm in longest diameter, visible on two or more axial slices, and at least 5 mm in diameter perpendicular to the longest diameter. Non-measurable disease includes lesions that are less than 10 mm, those with borders that are not able to be reproducibly measured, dural metastases, bony metastases, leptomeningeal metastases, and cystic-only lesions.
   2. Note, presence of measurable or non-measurable disease as per RECIST 1.1 assessed by the treating investigator/radiologist not required for eligibility.

6. There is no clinical indication for immediate local treatment with surgery or radiation therapy by the treating investigator's assessment.

7. Absence of documented leptomeningeal disease (LMD) by cytology. Note: clinical findings or neuroimaging indicating suspected LMD are allowed, so long as cerebrospinal fluid (CSF) cytology is negative.

8. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 0-1.

9. No restriction on the number of lines of prior systemic or local anticancer therapies

   1. Prior therapy must include treatment with an antibody-drug conjugate either per standard of care or as an investigational drug.

10. Life expectancy of at least three months (12 weeks) per treating investigator's assessment.

11. Adequate treatment washout period before C1D1, as outlined below:

    Major Surgery: minimum washout period of greater than or equal to 4 weeks Therapeutic or palliative stereotactic radiation therapy systemically or to CNS: minimum washout period of greater than or equal to 4 weeks Anticancer systemic therapy with immune checkpoint inhibitors: no washout period Anticancer system therapy including cytotoxic chemotherapy, and antibody-based therapy: minimum washout period of greater than or equal to 3 weeks Targeted agents and small molecules: minimum washout period of greater than or equal to 2 weeks or five half-lives, whichever is longer Strong cytochrome P450 (CYP3A4) inducers/inhibitors: minimum washout period of greater than or equal to 2 weeks Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines): minimum washout period of greater than 30 days. 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. If available, a mandatory agreement to provide an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion from any site. Fresh tissue collection is not required. There are no tissue biomarker requirements for study participation beyond the IHC subtype as described in the inclusion criteria.

13. Adequate organ function as defined below. Specimens must be collected within 72 hours before the start of the study intervention.

    Absolute Neutrophil Count greater than equal to 1500 per microliter of blood Platelet count greater than or equal to 100,000 per microliter of blood Hemoglobin count greater than or equal to 9.0 g/dL or greater than or equal to 5.6 mmol/L Measured or calculated creatine clearance greater than or equal to 30 mL/min Total bilirubin count less than or equal to 1.5 x ULN or direct bilirubin ≤ULN for participants with total bilirubin levels. >1.5 × ULN Aspartate aminotransferase(Serum Glutamic-Oxaloacetic Transaminase) and alanine aminotransferase(Serum Glutamate-Pyruvate Transaminase) count less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for participants with liver metastases) International normalized ratio or prothrombin time/partial thromboplastin time less than or equal to 1.5 x ULN

14. Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study.

15. HIV-infected participants must have well-controlled HIV on antiretroviral therapy (ART), defined as:

    1. Having a CD4+ T-cell count greater than or equal to 350 cells/mm3 at the time of screening.
    2. Having achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the LLOQ using the locally available assay, at the time of registration and for at least 12 weeks before registration.
    3. Absence of any AIDS-defining opportunistic infections within the past 12 months.
    4. Being on a stable regimen, without changes in drugs or dose modification, for at least four weeks before registration and agreeing to continue ART throughout the study.

    Note: The ART regimen must not contain any antiretroviral medications that are strong CYP3A4 inducers/inhibitors/substrates. The treating investigator should review the locally approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor/substrate of CYP3A4.

    e. HIV testing at screening is not required unless: i. There is a known history of HIV infection. ii. Mandated by local guidelines.

16. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least four weeks or have undetectable HBV viral load before registration.

    Note: Participants who are under treatment for HBV should remain on antiviral therapy throughout the study intervention and follow local guidelines for HBV antiviral therapy post-completion of the study intervention.

    1. Hepatitis B testing at screening is not required unless:

    i. There is a known history of HBV infection. ii. Mandated by local guidelines.

17. Participants with a history of HCV infection are eligible if the HCV viral load is undetectable at screening.

    a. Hepatitis C testing at screening is not required unless: i. There is a known history of HCV infection. ii. Mandated by local guidelines.

18. Participants must adhere to the following reproductive and contraceptive requirements while on study treatment and for 210 days after the last dose of the study drug:

    a. General Requirements: i. Participants must not be pregnant or breastfeeding. ii. Participants must not donate gametes (i.e., eggs or sperm) or freeze gametes for future use related to assisted reproduction.

    b. For participants of childbearing potential (POCBP): i. Participant of childbearing potential is defined as an individual who is premenopausal and capable of becoming pregnant, including those using contraception, those who are single, or those with partners who have had a vasectomy.

ii. A negative serum pregnancy test must be obtained at screening within 72 hours before the first dose of the study treatment, and participants must agree to further pregnancy tests throughout the study, if required.

iii. Participants must practice at least one highly effective method of contraception.

c. For Partners of Participants: i. If the participant's partner is of childbearing potential, the partner must also practice a highly effective method of contraception while the participant is on study treatment and for 120 days after the last dose of the study drug, unless the participant is vasectomized.

d. Highly effective methods of contraception include: i. Combined hormonal contraception (estrogen and progestogen) that inhibits ovulation (oral, intravaginal, or transdermal).

ii. Progestogen-only hormonal contraception that inhibits ovulation (oral, injectable, or implantable).

iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system. v. Bilateral tubal occlusion. vi. Sexual abstinence (the reliability of abstinence must be evaluated concerning the duration of the clinical study and the participant's lifestyle).

vii. A vasectomized partner (provided the partner is the sole sexual partner of the POCBP study participant and that the vasectomized partner has received medical confirmation of the surgical success).

Exclusion Criteria:

1. Prior use of sacituzumab tirumotecan.

2. Known hypersensitivity to sacituzumab tirumotecan or any of the drug components

3. Other concomitant anticancer therapy, including cytotoxic, targeted agents, immunotherapy, antibody, retinoid, or anti-cancer hormonal treatment with the exception of osteoprotective therapies such as denosumab or bisphosphonates.

   Note: Radiotherapy to CNS is allowed during the study if intracranial disease progresses clinically or radiologically without extracranial disease progression, with drug being held prior to radiation and a washout period of three weeks follows the end of radiation prior to resuming therapy.

4. A history of uncontrolled seizures (more than two seizures within 28 days prior to registration), CNS disorders, or psychiatric disability judged by the treating investigator to be clinically significant and adversely affecting compliance with study drug.

5. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses

6. Pregnant or lactating women.

7. Participants requiring concomitant use of chronic systemic (IV or oral) corticosteroids at doses higher than 8 mg dexamethasone per day or other immunosuppressive medications except for managing adverse events; inhaled steroids or intra articular steroid injections are permitted in this study.

8. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.

9. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF (Fridericia's formula) interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention.

10. Is currently enrolled in the active treatment phase of another therapeutic clinical trial.

11. Has a known additional malignancy that is systemically progressing.

12. Has an active infection requiring systemic therapy.

13. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual's ability to cooperate with the requirements of the study, or interfere with the individual's participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating investigator.

14. Has had major surgery or significant traumatic injury within four weeks before the first dose of study intervention.

    Note: Participants who underwent major surgery must have adequately recovered from toxicity and/or complications from the surgery before starting the study intervention.

15. Has current Grade >2 pneumonitis/interstitial lung disease.

16. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.

17. Is currently receiving a strong inducer/inhibitor of CYP3A4 that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks.