Sacituzumab Govitecan plus Nivolumab, with or without Relatlimab, as Second-Line Treatment in Patients with PD-L1 Positive Unresectable or Metastatic Triple Negative Breast Cancer, SIMONE Trial

Inclusion Criteria

• Must be competent and able to comprehend, sign, and date an Institutional Review Board (IRB) approved informed consent form (ICF) before the performance of any study specific procedures or tests
• Participants 18 years or older
• Pathologically documented breast cancer that: * Is defined as unresectable/metastatic disease * Is human epidermal growth factor receptor 2 (HER2)-negative, defined as HER2- immunohistochemistry (IHC) 0, 1+ or 2+ in situ hybridization (ISH) negative, and estrogen receptor (ER)- and progesterone receptor (PgR)- negative, both defined as IHC =< 10% * PD-L1 positive disease as per IHC via combined positive score (CPS) >= 10 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 Food and Drug Administration (FDA)-approved SP263 assay * Has been treated with up to one line of systemic cytotoxic chemotherapy with pembrolizumab in the metastatic setting. If recurrence occurred within six months of (neo)adjuvant chemotherapy, (neo)adjuvant chemotherapy would count as one line of therapy * Prior immune checkpoint inhibition with systemic chemotherapy is required in either neo(adjuvant) or metastatic settings * 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 enrollment
• 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
• Must have an adequate archival tumor sample < 3 years old available for assessment of PD-L1 status by IHC via CPS. If archival tissue is not available or inadequate for assessment (e.g., decalcified bone, cytology, or other), a fresh biopsy is required on enrollment
• Presence or absence of measurable lesion based on computed tomography (CT) or MRI per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1 are both allowed
• Eastern Cooperative Oncology Group (ECOG) performance score (PS) 0 or 1
• Left ventricular ejection fraction (LVEF) >= 50% within 6 months prior to enrollment
• Platelet count >= 75000/mm^3 (platelet transfusion is not allowed within 1 week prior to cycle 1 day 1 [C1D1]) (within 14 days from C1D1)
• Hemoglobin >= 9.0 g/dL (within 14 days from C1D1) * NOTE: Participants requiring more frequent than monthly ongoing transfusions or growth factor support to maintain hemoglobin >= 9.0 g/dL are not eligible. Red blood cell transfusion is not allowed within 1 week prior to C1D1
• Absolute neutrophil count >= 1000/mm^3 (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1) (within 14 days from C1D1)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) (< 5 x ULN in participants with liver metastases) (within 14 days from C1D1)
• Total bilirubin =< 1.5 x ULN if no liver metastases or =< 3 x ULN in the presence of liver metastases at baseline (within 14 days from C1D1)
• Creatinine clearance (CrCL) >= 30 mL/min as determined by Cockcroft Gault (using actual body weight) (within 14 days from C1D1)
• International normalized ratio or prothrombin time =< 1.5 x ULN (except if patients are on oral anticoagulation, when this should be =< 3 x ULN) (within 14 days from C1D1)
• Troponin: Troponin T (TnT) or I (TnI) > 2 x institutional ULN. Participants with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the participant may undergo a cardiac evaluation and be considered for treatment, following a discussion with the sponsor-investigator. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the participant may undergo a cardiac evaluation and be considered for treatment, following a discussion with the sponsor-investigator (within 14 days from C1D1)
• Creatine phosphokinase (CPK) < 2 x ULN will be permitted (within 14 days from C1D1)
• Adequate contraception when indicated, such as: * 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 * 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 * 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 postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause * Participants of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for seven months after the last dose of study drugs * Female participants must refrain from breastfeeding while on study and for seven months after the last dose of study drugs * Female participants must not donate, or retrieve for their own use, ova from the time of enrollment 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 enrollment in this study * 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 * 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 * Male participants should refrain from fathering a child or freezing or donating sperm from the time of enrollment, throughout the study, and for five months after the last dose of study drugs. Preservation of sperm should be considered prior to enrollment in this study Highly effective methods of contraception (< 1% failure rate): * Non-hormonal methods: ** Total heterosexual abstinence (evaluate in relation to the duration of the clinical study and the preferred and usual lifestyle choice of the participant) ** Vasectomized sexual partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success) ** Bilateral tubal occlusion ** Intrauterine device (provided coils are copper banded) * Hormonal methods: ** Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: *** Oral *** Intravaginal *** Transdermal ** Progestogen-only hormonal contraception associated with inhibition of ovulation: *** Oral *** Injectable *** Implantable ** Intrauterine hormone-releasing system (IUS)

Exclusion Criteria

• Participants who are pregnant or lactating
• Participants of childbearing potential or fertile men unwilling to use effective contraception
• Certain prior comorbidities, such as: * Concomitant metastatic disease from other primary tumors * Known history of unstable angina, myocardial infarction (MI), or congestive heart failure (CHF) present within six months of randomization or clinically significant cardiac arrhythmia (other than stable atrial fibrillation) requiring anti-arrhythmia therapy * History of myocarditis * Known history of clinically significant active chronic obstructive pulmonary disease (COPD), or other moderate-to-severe chronic respiratory illness present within six months of randomization * 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 * Prior history of gastrointestinal (GI) perforation within six months of randomization * Has an uncontrolled infection requiring current IV antibiotics, antivirals, or antifungals * Has known human immunodeficiency virus (HIV) infection with detectable viral load or CD4 count < 200 cells per cubic millimeter or active hepatitis B (hepatitis B virus surface antigen [HBsAg] positive) or C (hepatitis C virus [HCV] positive ribonucleic acid [RNA]) infection * Any active autoimmune, connective tissue or inflammatory disorders that required active immunomodulatory or corticosteroid treatments in the two years prior to study enrollment. 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
• Certain central nervous system conditions, such as: * Has currently untreated spinal cord compression * Has clinically active central nervous system metastases, defined as symptomatic, or requiring therapy with corticosteroids to control associated symptoms * 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 * 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
• 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, residual endocrinopathies from use of immunotherapy such as hypothyroidism/hyperthyroidism, type 1 diabetes, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation [vitiligo])
• 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
• Participants must not have had prior treatment with relatlimab or any other LAG-3 targeted agent, as well as no prior sacituzumab govitecan (SG)
• 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
• Adequate washout period from prior therapies before C1D1 as follows: * Major surgery: >= 4 weeks * Therapeutic radiation therapy, and palliative stereotactic radiation therapy to chest: >= 4 weeks * Palliative stereotactic radiation therapy to other anatomic areas besides chest, including whole brain radiation: >= 2 weeks * Anticancer systemic therapy with immune checkpoint inhibitors: >= 4 weeks * Anticancer systemic therapy including cytotoxic chemotherapy, and antibody-based therapy: >= 3 weeks * Targeted agents and small molecules: >= 2 weeks or five half-lives, whichever is longer * Strong cytochrome P450 (CYP3A4) and organic anion transporting polypeptide (OATP) inhibitors: >= 3 elimination half-lives of the inhibitor is required * Receipt of live, attenuated vaccine (messenger RNA [mRNA] and replication deficient adenoviral vaccines are not considered attenuated live vaccines): >= 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 * Drainage of pleural effusion or ascites: no washout required * Drainage of pericardial effusion: >= 2 weeks