Testing the Addition of Pembrolizumab to Sacituzumab Govitecan for the Treatment of PD-L1 Negative Locally Advanced Unresectable or Metastatic Triple Negative Breast Cancer, Saci-IO TNBC Study

Inclusion Criteria

• Participants must have histologically or cytologically confirmed invasive breast cancer with unresectable locally advanced or metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation
• Estrogen-receptor and progesterone-receptor expression both =< 5% by immunohistochemistry (IHC), and HER2-negative status as determined by the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. If a patient has more than one histological result, the most recent sample will be considered for inclusion
• Participants must have PD-L1-negative metastatic breast cancer defined as less than 1% expression of PD-L1 on tumor-infiltrating immune cells (IC) by the PD-L1 IHC SP142 assay or a combined positive score (CPS) less than 10 by the PD-L1 IHC 22C3 assay measured with standard of care testing. If testing is performed with both PD-L1 IHC SP142 and PD-L1 IHC 22C3 on the same sample used to determine eligibility, the results should be negative by both assays
• Participants must have evaluable or measurable disease per RECIST 1.1
• Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline. Previously collected archival tissue will also be requested, if available, for all participants. A source of archival tumor tissue should be identified at time of registration. Participants must agree to a mandatory repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible
• Participants must be treatment-naive in the metastatic setting
• Prior chemotherapy: participants must have received no prior chemotherapy for metastatic breast cancer and must have discontinued all chemotherapy at least 14 days prior to study treatment initiation (any prior endocrine therapy does not require washout). All toxicities related to prior chemotherapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade 1 or lower, except alopecia can be any grade and neuropathy can be grade 2 or lower
• Prior biologic or targeted therapy: patients must have received no prior biologic tor targeted therapy for metastatic breast cancer and must have discontinued all biologic or targeted therapy (e.g., neoadjuvant or adjuvant CDK 4/6 inhibitors) at least 14 days prior to study treatment initiation. All toxicities related to prior biologic or targeted therapy must have resolved to CTCAE v5.0 grade 1 or lower
• Prior investigational therapy: Patients must have received no prior investigational agents for metastatic breast cancer and must have discontinued all investigational agents >= 14 days prior to initiation of study therapy. All toxicities related to prior investigational agents must have resolved to CTCAE v5.0 grade 1 or lower
• Prior radiation therapy: patients may have received prior radiation therapy. Radiation therapy must be completed at least 7 days prior to study treatment initiation, and all toxicities related to prior radiation therapy must have resolved to CTCAE v5.0 grade 1 or lower. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (non-central nervous system [CNS]) disease
• Previously treated brain metastases are permitted, with the following provisions: * Prior stereotactic radiosurgery (SRS) should complete >= 7 days before study treatment initiation * Prior whole brain radiotherapy (WBRT) or stereotactic body radiation therapy (SBRT) should complete >= 7 days before study treatment initiation * Any corticosteroid use for brain metastases must have been discontinued for >= 7 days prior to study treatment initiation
• Patients with new or progressive brain metastases (active brain metastases) are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy, there is no requirement for corticosteroids, and the patient is asymptomatic
• The subject is >= 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky > 60%)
• Absolute neutrophil count >= 1,500/mcL (criteria must be met without erythropoietin dependency and without packed red blood cells)
• Platelets >= 100,000/mcL (criteria must be met without erythropoietin dependency and without packed red blood cells)
• Hemoglobin >= 9.0 g/dl (criteria must be met without erythropoietin dependency and without packed red blood cells)
• International normalized ratio/ prothrombin time/partial thromboplastin time (INR/PT/aPTT) =< 1.5 x upper limit of normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or aPTT is in therapeutic range of anticoagulant (criteria must be met without erythropoietin dependency and without packed red blood cells)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.0 x ULN in patients with documented Gilbert’s Syndrome) (criteria must be met without erythropoietin dependency and without packed red blood cells)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN or =< 5 × institutional ULN for participants with documented liver metastases (criteria must be met without erythropoietin dependency and without packed red blood cells)
• Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 30 mL/min/ 1.73m^2 for participants with creatinine levels above institutional ULN
• Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation. Childbearing potential is defined as participants who have not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus)
• Women of childbearing potential (WOCBP) must agree to use an adequate method of contraception. Contraception is required starting with the first dose of study medication through 180 days (6 months) after the last dose of study medication. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with pembrolizumab and 3 months after the last dose of study treatment
• Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment and also may initiate therapy with these agents on study if clinically indicated
• The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document

Exclusion Criteria

• Prior therapy with any anti-PD-1, PD-L1, or PD-L2 agent or sacituzumab govitecan (IMMU-132). Prior therapy with irinotecan or topoisomerase I-containing antibody drug conjugates at any time
• Prior hypersensitivity to pembrolizumab or the excipients of pembrolizumab or sacituzumab govitecan (IMMU-132 therapy)
• Known history of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28 allele homozygosity, which is associated with increased risk for neutropenia and diarrhea related to irinotecan * Note: Concurrent administration of strong UGT1A1 inhibitors or inducers is not allowed during the course of the study
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
• Participant has known leptomeningeal disease
• Major surgery within 2 weeks prior to study treatment initiation. Patients must have recovered from any effects of any major surgery
• Uncontrolled, significant intercurrent or recent illness including, but not limited to, ongoing or active infection, uncontrolled non-malignant systemic disease, uncontrolled seizures, or psychiatric illness/social situation that would limit compliance with study requirements in the opinion of the treating investigator
• Participant has a medical condition that requires chronic systemic steroid therapy (> 10 mg of prednisone daily or equivalent) or any other form of immunosuppressive medication (including disease modifying agents) and has required such therapy in the last 2 years. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic therapy
• Participant has documented history of autoimmune disease or syndrome that currently requires systemic steroids or immunosuppressive agents
• History of (non-infectious) pneumonitis//interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
• Individuals with a history of a second malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers that have been diagnosed and treated within the past 3 years are eligible: cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer of the skin. Patients with other cancers diagnosed within the past 3 years and felt to be at low risk of recurrence should be discussed with the study principal investigator to determine eligibility
• Participant has a known history of human immunodeficiency virus (HIV), hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as detected HCV ribonucleic acid [RNA] [qualitative]) infection. HIV-positive participants are ineligible due to the potential for pharmacokinetic interactions of combination antiretroviral therapy with study drugs and the increased risk of fatal infections when treated with marrow-suppressive therapy. Note: No testing for HIV, hepatitis B, or hepatitis C is required unless mandated by local health authority
• The participant has received a live vaccine within 28 days prior to study treatment initiation. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. The use of the inactivated seasonal influenza vaccine is allowed
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, participants who are breast-feeding are not eligible for enrollment