Inclusion Criteria:

• Signed Informed Consent Form.
• Age ≥ 18 years at the time of signing Informed Consent Form.
• Metastatic or locally advanced unresectable, histologically documented TNBC (absence of HER2-over-expression, ER, and PgR expression by local assessment): 
  • HER2 negativity (it is recommended that labs follow American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) HER2 testing guidelines, and interpret as follows) by local laboratory assessment:
    • In situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell); or
    • IHC 0.
  • HER2-low-status (it is recommended that labs follow ASCO-CAP HER2 testing guidelines, and interpret as follows) by local laboratory assessment:
    • IHC 2 + and in situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell); or
    • IHC 1+ (and not required, but if performed, in situ hybridization non-amplified [ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell]);
  • ER and PgR negativity are defined as < 1% of cells expressing hormonal receptors via IHC analysis, with testing to be performed locally.
• Measurable disease per RECIST v1.1.
• If metastatic disease (Stage IV), measurable disease outside of the bone.
• Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that same lesion since radiation.
• No prior systemic therapy for metastatic or locally advanced unresectable TNBC:
  • Radiation therapy for metastatic disease is permitted. There is no required minimum washout period for radiation therapy. Participants should have recovered from the effects of radiation;
  • Prior systemic therapy for early breast cancer (resectable and nonmetastatic, in the neoadjuvant and/or adjuvant setting) is permitted. If prior systemic therapy was given for early TNBC, it must have included anthracycline and taxane;
  • Prior systemic therapy for early breast cancer is permitted if treatment was completed ≥ 12 months prior to initiation of study treatment (Cycle 1, Day 1);
  • Prior anti-PD-1 or anti-PD-L1 therapeutic antibody exposure (e.g., atezolizumab or pembrolizumab) in the neoadjuvant and/or adjuvant setting is allowable if treatment was completed ≥ 12 months prior to initiation of study treatment (Cycle 1, Day 1).
• Tumor PD-L1 expression as documented through central testing of a representative tumor tissue specimen:
  • An FFPE tumor specimen in a paraffin block (preferred) or at least 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report. Tumor tissue must be obtained from a biopsy performed within the 3 months prior to consent. If no tumor tissue collected within the 3 months prior to consent is available, fresh tissue may be obtained or archival tissue may be used. Bone is not an acceptable source of tumor tissue;
  • Tumor tissue should be of good quality based on total and viable tumor content and must be evaluated at a central laboratory for PD-L1 expression and determined to be positive, as determined using the investigational VENTANA PD-L1 (SP263) Assay and the Dako PD-L1 IHC 22C3 pharmDx assay, prior to randomization. Positivity is defined as ≥ 5% of the tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells of any intensity (TAP 5%) or a CPS of ≥ 10, respectively. Positivity by either or both assays is required for randomization. See Section 8.7 for additional information on tumor specimens collected at screening.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see Appendix 9).
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
  • ANC ≥ 1.5 × 10^9 /L (1500/µL) without granulocyte colony-stimulating factor (G-CSF) support within the prior 14 days with one exception:
    • Participants with a benign ethnic neutropenia (BEN): ANC < 1.3 × 10^9 /L (1300/mL):
      • BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al. 2019). BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups;
      • Participants with BEN are eligible, but this must be documented in the General Medical History in the eCRF;
      • Participants with BEN must not have received GCSF support within the prior 14 days.
    • Lymphocyte count ≥ 0.5 × 10^9 /L (500/mL);
    • Platelet count ≥ 100 × 10^9 /L (100,000/mL) without transfusion within the prior 14 days;
    • Hemoglobin ≥ 90 g/L (9 g/dL) without transfusion within the prior 14 days;
    • AST, ALT, and ALP ≤ 2.5 × upper limit of normal (ULN), with the following exceptions: With documented liver metastases: AST and ALT ≤ 5 × ULN. With documented liver or bone metastases: ALP ≤ 5 × ULN;
    • Total bilirubin ≤ 1.5 × ULN with the following exception: Known Gilbert disease: total bilirubin ≤ 3 × ULN. Albumin ≥ 25 g/L (2.5 g/dL);
    • Not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 × ULN;
    • Receiving therapeutic anticoagulation: a stable anticoagulant regimen.
• Negative HIV test at screening, with the following exception: individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/mL, and have an undetectable viral load.
• Negative hepatitis B surface antigen (HBsAg) test at screening.
• Positive hepatitis B surface antibody (HBsAb) test at screening, or a negative HBsAb at screening accompanied by either of the following:
  • Negative hepatitis B core antibody (HBcAb);
  • Positive HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL The HBV DNA test must be performed for individuals who have a negative HBsAg test, a negative HBsAb test, and a positive HBcAb test.
• Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening:
  • The HCV RNA test must be performed for individuals who have a positive HCV antibody test.
• Adequate cardiovascular function:
  • New York Heart Association (NYHA) Heart Failure Class ≤ 2;
  • Baseline-corrected QT (QTcF) interval ≤ 480 ms. If the QTcF interval is longer than 480 ms but shorter than 500 ms, the participant may undergo a cardiac evaluation and be considered for treatment in case of no clinically significant findings;
  • Resting systolic blood pressure ≤150 mmHg and diastolic blood pressure 100 mmHg (average of  ≥ 3 readings on ≤ 2 sessions with short break between sessions) (or no clinically significant hypertension);
  • Resting heart rate (HR) between 45 and 100 bpm (or no clinically significant tachycardia);
  • LVEF ≥ 50% assessed by either transthoracic echocardiogram (TTE) or MUGA (TTE preferred test) within 6 months before first study drug administration;
  • TnT or I (TnI) ≤ institutional upper limit of normal (ULN). Participants with TnT or TnI levels between >1 and < 2 × ULN will be permitted to enter the study if repeat levels are ≤ 1 × ULN. If repeat levels are between > 1 and < 2 × ULN, the participants need to undergo a cardiac evaluation and can be considered for treatment in case of no clinically significant findings.
• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agree to refrain from donating eggs, as defined below:
  • Female participants must remain abstinent or use contraceptive methods with a failure rate of  ≤ 1% per year during the treatment period and for 4 months after the final dose of RO7247669 or pembrolizumab and for 6 months after the final dose of nab-paclitaxel. Participants must refrain from donating eggs during this same period. A female participant is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (³ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a female participant with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined below:
  • With a female partner of childbearing potential or pregnant female partner, male participants must remain abstinent or use a condom during the treatment period and for 4 months after the final dose of RO7247669 or pembrolizumab and 6 months after the final dose of nab-paclitaxel to avoid exposing the embryo. Male participants must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

Exclusion Criteria:

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 4 months after the final dose of RO7247669 or pembrolizumab, and 6 months after the final dose of nab-paclitaxel:
  • Female participants of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
• Poor venous access.
• Glomerular filtration rate (GFR) < 30 mL/min/1.73 m^2 as calculated through use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation:
  • GFR should be assessed by calculation through use of the CKD-EPI equation:
    • CKD‑EPI = 142 × (serum creatinine/A)B × 0.9938Age × (1.012 if female), where A and B are the following:
      • Female serum creatinine ≤ 0.7 mg/dL: A= 0.7 and B= -0.241;
      • Female serum creatinine > 0.7 mg/dL: A= 0.7 and B= -1.2;
      • Male serum creatinine ≤ 0.9 mg/dL: A= 0.9 and B= -0.302;
      • Male serum creatinine > 0.9 mg/dL: A= 0.9 and B = -1.2.
• History of malignancy within 5 years prior to consent, except for the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases:
  • Asymptomatic participants with treated CNS lesions are eligible if all of the following criteria are met:
    • Measurable disease, per RECIST v1.1, must be present outside the CNS;
    • The participant has no history of intracranial hemorrhage or spinal cord hemorrhage;
    • The participant has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment;
    • The participant has no ongoing requirement for corticosteroids as therapy for CNS disease;
    • If the participant is receiving anti-convulsant therapy, the dose is considered stable (per the investigator’s judgment);
    • Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord);
    • No evidence of significant vasogenic edema;
    • There is no evidence of interim progression (per the investigator’s judgment) between completion of CNS-directed therapy and initiation of study treatment;
    • Asymptomatic participants with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy and/or surgery, with no need to repeat the screening brain scan.
• History of leptomeningeal disease.
• Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently):
  • Participants with indwelling catheters (e.g., PleurXâ) are allowed.
• Hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN) or hypercalcemia that is symptomatic.
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 10 for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:
  • Participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study;
  • Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study;
  • Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met:
    • Rash must cover < 10% of body surface area;
    • Disease is well-controlled at baseline and requires only low-potency topical corticosteroids;
    • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within12 months prior to consent.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Active tuberculosis (as defined per local standard of care).
• Significant cardiovascular/cerebrovascular disease within 3 months prior to consent, including any of the following:
  • Hypertensive crisis or encephalopathy;
  • Unstable angina;
  • Transient ischemic attack/stroke o Congestive heart failure (for NYHA classification, refer to inclusion criteria);
  • Serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, paroxysmal supraventricular tachycardia);
  • History of thromboembolic events (such as myocardial infarction, stroke or pulmonary embolism).
• History or presence of an abnormal ECG that is deemed clinically significant, (e.g., complete left bundle branch block, second- or third-degree atrioventricular heart block) or evidence of prior myocardial infarction.
• QT interval corrected through use of Fridericia's formula (QTcF) > 480 ms demonstrated by at least two ECGs > 30 minutes apart.
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.
• Major surgical procedure within 4 weeks prior to initiation of study treatment:
  • Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure.
• Treatment with therapeutic oral or IV antimicrobials (anti-bacterial, anti-fungal, antiviral, anti-parasitic) within 1 week prior to initiation of study treatment:
  • Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for the study.
• Prior allogeneic stem cell or solid organ transplantation.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications.
• Treatment with a live, attenuated vaccine within 28 days prior to initiation of study treatment.
• Treatment with investigational therapy within 28 days prior to initiation of study treatment.
• Prior treatment with CD137 agonists or anti-CTLA therapeutic antibodies or an anti-LAG3 agent.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including, but not limited to, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to initiation of study treatment:
  • Participants who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or 48 hours of corticosteroids for a contrast allergy) are eligible for this study;
  • Participants with a history of allergic reaction to IV contrast requiring steroid pretreatment should have baseline and subsequent tumor assessments performed receiving magnetic resonance imaging (MRI);
  • The use of inhaled corticosteroids for COPD, mineralocorticoids (e.g., fludrocortisone) for participants with orthostatic hypotension, and low‑dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the RO7247669 or pembrolizumab formulation.
• Known allergy or hypersensitivity to any component of the to nab-paclitaxel formulation.