This is a randomized, open-label, phase Ib study to assess safety and efficacy of sacituzumab govitecan plus nivolumab or sacituzumab govitecan plus a fixed dose combination of nivolumab and relatlimab in patients with any programmed cell death-ligand 1 (PD-L1) status metastatic, triple negative breast cancer on routine testing with one prior line of cytotoxic chemotherapy with or without immunotherapy in the metastatic setting. The study treatment will be continued until the progression of disease, unacceptable toxicity, death, or withdrawal of consent for any reason.

This is a randomized, open-label, phase Ib study to assess safety and efficacy of sacituzumab govitecan plus nivolumab or sacituzumab govitecan plus a fixed dose combination of nivolumab and relatlimab in patients with any programmed cell death-ligand 1 (PD-L1) status metastatic, triple negative breast cancer on routine testing with one prior line of cytotoxic chemotherapy with or without immunotherapy in the metastatic setting. The study treatment will be continued until the progression of disease, unacceptable toxicity, death, or withdrawal of consent for any reason. Patients will be followed up for up to two years. Their safety will be monitored, and tumor response will be regularly evaluated by RECIST 1.1 criteria every nine weeks. The primary endpoint includes safety as the incidence of dose-limiting toxicities (DLT) in three weeks after C1D1. Secondary endpoints include overall response rate (defined as either complete response or partial response), duration of response, clinical benefit rate, progression free survival, and safety (TEAE) with sacituzumab govitecan plus nivolumab or sacituzumab govitecan plus nivolumab + relatlimab FDC. Exploratory endpoints include overall survival, and biomarkers of prediction of response will be also evaluated. There will be a 135-day (+7 days) follow-up visit after the last study treatment administration or before starting a new anticancer treatment, whichever occurs first, followed by long-term/survival chart review follow-up every three months (±14 days) from the date of the 135-day (+7 days) follow-up visit for two years.

Inclusion Criteria:

1. Must be competent and able to comprehend, sign, and date an IRB approved ICF before the performance of any study specific procedures or tests.

2. Participants 18 years or older.

3. Pathologically documented breast cancer that:

   1. Is defined as unresectable/metastatic disease.
   2. Is Human Epidermal Growth Factor Receptor 2 (HER2)-negative, defined as HER2- immunohistochemistry (IHC) 0, 1+ or 2+ ISH negative, and estrogen receptor (ER)- and progesterone receptor (PgR)- negative, both defined as IHC <10%
   3. Any PD-L1 status measured by IHC via CPS by IHC (defined by the number of PD-L1 staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100) via FDA-approved SP263 assay.
   4. Has been treated with up to one line of systemic cytotoxic chemotherapy with or without immunotherapy in the metastatic setting. If recurrence occurred within six months of (neo)adjuvant chemotherapy, (neo)adjuvant chemotherapy would count as one line of therapy.
   5. Prior immune checkpoint inhibition with systemic chemotherapy is required in either neo(adjuvant) or metastatic settings
   6. Prior targeted therapies (e.g., olaparib, or others upon discussion with study sponsor-investigator) do not count as systemic cytotoxic chemotherapy lines and are unlimited prior to enrolment.

4. Documented radiologic progression (during or after most recent treatment) or intolerance to prior line of therapy regardless of prior response with subsequent medical need for change of therapy.

5. Must have an adequate archival tumor sample <3 years old available for exploratory analyses. If archival tissue is not available or inadequate for assessment (e.g., decalcified bone, cytology, or other), a new tissue biopsy is required on enrolment.

6. Presence or absence of measurable lesion-based Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 are both allowed.

7. ECOG PS 0 or 1.

8. Left ventricular ejection fraction (LVEF) ≥50% within 6 months prior to enrolment.

9. Adequate laboratory parameters (table 1) within 14 days from C1D1

10. Adequate contraception when indicated (table 2), such as:

    1. Evidence of post-menopausal status or negative serum pregnancy test for participants of childbearing potential who are sexually active with a non-sterilized male partner.
    2. For participants of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of study drugs.
    3. Participants of childbearing potential are defined as those who are not surgically sterile (i.e., underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Participants will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
    4. Participants of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in table 3, from the time of screening and must agree to continue using such precautions for seven months after the last dose of study drugs.
    5. Female participants must refrain from breastfeeding while on study and for seven months after the last dose of study drugs.
    6. Female participants must not donate, or retrieve for their own use, ova from the time of enrolment and throughout the study treatment period, and for at least seven months after the final study drug administration. Preservation of ova may be considered prior to enrolment in this study.
    7. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the participant's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic, or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.
    8. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a condom from screening to five months after the final dose of study drugs.
    9. Male participants should refrain from fathering a child or freezing or donating sperm from the time of enrolment, throughout the study, and for five months after the last dose of study drugs. Preservation of sperm should be considered prior to enrolment in this study.

Exclusion Criteria:

Participants who meet any of the following criteria will be disqualified from entering the study:

1. Participants who are pregnant or lactating.

2. Participants of childbearing potential or fertile men unwilling to use effective contraception.

3. Certain prior comorbidities, such as:

   1. Concomitant metastatic disease from other primary tumors.
   2. Known history of unstable angina, MI, or CHF present within six months of randomization or clinically significant cardiac arrhythmia (other than stable atrial fibrillation) requiring anti-arrhythmia therapy.
   3. History of myocarditis.
   4. Known history of clinically significant active COPD, or other moderate-to-severe chronic respiratory illness present within six months of randomization.
   5. History of (non-infectious) pneumonitis or interstitial pulmonary disease that required steroids for more than 28 consecutive days or has current pneumonitis or interstitial pulmonary disease.
   6. Prior history of GI perforation within six months of randomization.
   7. Has an uncontrolled infection requiring current IV antibiotics, antivirals, or antifungals.
   8. Has known 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.
   9. Any active autoimmune, connective tissue or inflammatory disorders that required active immunomodulatory or corticosteroid treatments in the two years prior to study enrolment. Participants with active autoimmune diseases may enroll with the following conditions: type 1 diabetes mellitus; hypothyroidism only requiring hormone replacement; skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment.

4. Certain central nervous system conditions, such as:

   1. Has currently untreated spinal cord compression.
   2. Has clinically active central nervous system metastases, defined as symptomatic, or requiring therapy with corticosteroids to control associated symptoms.
   3. Participants with clinically asymptomatic brain metastases not requiring corticosteroids and seizure-free for more than 30 days with or without prior local therapy administration (surgery and/or radiation therapy) may be included in the study.
   4. Participants 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.

5. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade ≤1 or baseline. Participants 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)).

6. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.

7. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.

8. Participants must not have had prior treatment with relatlimab or any other LAG-3 targeted agent, as well as no prior SG or other TROP2-ADCs..

9. Substance abuse, medical conditions, social, familial, or geographical factors that would, in the opinion of the investigator, increase the safety risk to the participant or interfere with the participant's participation in the clinical study or evaluation of the clinical study results despite best use of locally and community available resources.

10. Adequate washout period from prior therapies before C1D1