Sacituzumab Govitecan +/- Pembrolizumab in Metastatic TNBC

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed invasive breastcancer with unresectable locally advanced or metastatic disease. Participantswithout pathologic or cytologic confirmation of metastatic disease should haveunequivocal evidence of metastasis from physical examination or radiologicevaluation.

• Estrogen-receptor and progesterone-receptor expression both ≤ 5% byimmunohistochemistry (IHC), and HER2-negative status as determined by the currentASCO/CAP guidelines. If a patient has more than one histological result, the mostrecent 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 IHCSP142 assay or a Combined Positive Score (CPS) less than 10 by the PD-L1 IHC 22C3assay measured with standard of care testing.

• Participants must be treatment-naïve in the metastatic setting.

• Participants must have evaluable or measurable disease per RECIST 1.1. Patients withbone only disease will be allowed to participate.

• Participants must agree to undergo a research biopsy, if tumor is safely accessible,at baseline. Previously collected archival tissue will also be obtained on allparticipants. Tissue needs to be located and availability confirmed at time ofregistration (see Section 9 for more details). Participants must agree to amandatory repeat biopsy 3-6 weeks after starting treatment, if tumor is safelyaccessible.

• Prior chemotherapy: Participants must have received no prior chemotherapy formetastatic breast cancer and must have discontinued all chemotherapy at least 28days prior to study treatment initiation. No prior irinotecan or topoisomeraseI-containing antibody drug conjugates in the metastatic or neo/adjuvant setting areallowed. All toxicities related to prior chemotherapy must have resolved to CTCAEv5.0 grade 1 or lower, unless otherwise specified per protocol, except alopecia canbe any grade and neuropathy can be grade 2 or lower.

• Prior biologic therapy: Patients must have received no prior biologic therapy formetastatic breast cancer and discontinued all biologic therapy at least 28 daysprior to study treatment initiation. All toxicities related to prior biologictherapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwisespecified per protocol.

• Prior radiation therapy: Patients may have received prior radiation therapy.Radiation therapy must be completed at least 7 days prior to study treatmentinitiation, and all toxicities related to prior radiation therapy must have resolvedto CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol. A 1-weekwashout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNSdisease.

• Previously treated brain metastases are permitted, with the following provisions:

• Prior SRS should complete ≥ 7 days before study treatment initiation

• Prior WBRT should complete ≥ 7 days before study treatment initiation.

• Any corticosteroid use for brain metastases must have been discontinued for ≥ 7days prior to study treatment initiation.

• The subject is ≥ 18 years old.

• ECOG performance status 0-1 (Karnofsky > 60%, see Appendix A).

• Participants must have normal organ and marrow function as defined below:

• Absolute neutrophil count ≥1,000/mcL

• Platelets ≥100,000/mcL

• Hemoglobin ≥ 9.0 g/dl

• INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy aslong as PT or aPTT is in therapeutic range of anticoagulant

• Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)(or ≤2.0 x ULNin patients with documented Gilbert's Syndrome)

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤5 × institutional ULN forparticipants with documented liver metastases

• Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/ 1.73m2 for participants with creatinine levels above institutional ULN.

• Female subjects of childbearing potential must have a negative serum or urinepregnancy test within 2 weeks prior to study treatment initiation. Childbearingpotential 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 ofcontraception. Contraception is required starting with the first dose of studymedication through 180 days (6 months) after the last dose of study medication.Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, established and proper use of hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices, andcopper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation,symptothermal, or postovulation methods) and withdrawal are not acceptable methodsof contraception.

• Males who are sexually active with WOCBP must agree to follow instructions formethod(s) of contraception for the duration of study treatment with pembrolizumaband 3 months after the last dose of study treatment

• Participants on bisphosphonates or RANK ligand inhibitors may continue receivingtherapy during study treatment and also may initiate therapy with these agents onstudy if clinically indicated.

• The participant must be capable of understanding and complying with the protocol andwilling to sign a written informed consent document.

Exclusion Criteria:

• Has received prior systemic anti-cancer therapy, including investigational agents,within 4 weeks of study treatment initiation or during the course of this study (bisphosphonates and RANK ligand inhibitors are allowed).

• 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 antibodydrug conjugates at any time for early stage or metastatic disease.

• Prior hypersensitivity to pembrolizumab or the excipients of pembrolizumab orsacituzumab 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 toirinotecan. Note: Concurrent administration of strong UGT1A1 inhibitors or inducersis not allowed during the course of the study.

• Known brain metastases that are untreated, symptomatic, or require therapy tocontrol symptoms.

• Major surgery within 2 weeks prior to study treatment initiation. Patients must haverecovered from any effects of any major surgery.

• Uncontrolled, significant intercurrent or recent illness including, but not limitedto, ongoing or active infection, uncontrolled non-malignant systemic disease,uncontrolled seizures, or psychiatric illness/social situation that would limitcompliance 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 immunosuppressivemedication (including disease modifying agents) and has required such therapy in thelast 2 years. Replacement therapy (e.g. thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) isnot considered a form of systemic therapy.

• Participant has documented history of autoimmune disease or syndrome that currentlyrequires systemic steroids or immunosuppressive agents.

• History of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

• Individuals with a history of a second malignancy are ineligible except for thefollowing circumstances. Individuals with a history of other malignancies areeligible if they have been disease-free for at least 3 years or are deemed by theinvestigator to be at low risk for recurrence of that malignancy. Individuals withthe following cancers that have been diagnosed and treated within the past 3 yearsare eligible: cervical/prostate carcinoma in situ, superficial bladder cancer,non-melanoma cancer of the skin. Patients with other cancers diagnosed within thepast 3 years and felt to be at low risk of recurrence should be discussed with thestudy 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 HepatitisC virus (defined as detected HCV RNA [qualitative]) infection. HIV-positiveparticipants are ineligible due to the potential for pharmacokinetic interactions ofcombination antiretroviral therapy with study drugs and the increased risk of fatalinfections 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 treatmentinitiation. Examples of live vaccines include, but are not limited to, thefollowing: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, andtyphoid vaccine. The use of the inactivated seasonal influenza vaccine is allowed.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest 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 areexcreted in human milk, and because of the potential for serious adverse reactionsin the nursing infant, participants who are breast-feeding are not eligible forenrollment.