Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy for HR+/HER2- Locally Recurrent Inoperable or Metastatic Breast Cancer (MK-3475-B49/KEYNOTE-B49)

The key inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Has locally recurrent inoperable or metastatic HR+/HER2- breast cancer, which hasnot been previously treated with cytotoxic chemotherapy in the noncurative setting

• Has progressed on prior endocrine therapy and is now a chemotherapy candidate,meeting the characteristics in regard to previous treatments of one of the following 4 groups:

• Group 1: Has progressed on 2 or more lines of endocrine therapy foradvanced/metastatic HR+/HER2-disease, with at least given in combination with aCyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Prior treatment with mTOR and/orPI3-K inhibitors is allowed. OR

• GROUP 2a: Has progressed on 1 line of previous endocrine therapy foradvanced/metastatic disease AND had a disease recurrence within 24 months ofdefinitive surgery for the primary tumor and while on adjuvant endocrine therapy.Prior use of CDK4/6 inhibitors is required, either in the adjuvant and/or metastaticsetting. Prior treatment with mTOR and/or PI3-K inhibitors is allowed. OR

• GROUP 2b: Has progressed within 12 months of starting 1 line of endocrine therapywith a CDK4/6 inhibitor for advanced/metastatic HR+/HER2- disease. OR

• GROUP 3: If no prior treatment with a CDK4/6 inhibitor, for advanced/metastaticdisease and/or early stage disease (adjuvant), participants must have progressedwithin 6 months of starting 1 line of endocrine therapy with or without an mTOR orPI3-K inhibitor for metastatic disease AND had a relapse within 24 months ofdefinitive surgery for primary tumor and while receiving adjuvant endocrine therapy.

• Has presented a documented radiographic disease progression (as assessed by theinvestigator and/or histology [biopsy or cytology] for participants presenting withnew metastatic lesions) during or after the last administered endocrine therapyprior to entering the study.

• Is a chemotherapy candidate that meets the criteria specified in the protocol

• Provides a new or the last obtained core biopsy, preferably consisting of multiplecores, taken from a locally recurrent or a distant (metastatic) lesion notpreviously irradiated

• Has centrally confirmed PD-L1 CPS ≥1 and HR+ (estrogen receptor [ER] and/orprogesterone receptor [PgR]) /HER2- breast cancer as defined by the most recentAmerican Society of Clinical Oncology (ASCO)/(College of American Pathologists) CAPguidelines on most recent tumor biopsy

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, asassessed within 7 days prior to the first dose of study treatment

• Has adequate organ function within 10 days prior to the start of study

• Male participants must agree to the following during the treatment period and for atleast 6 months after the last dose of chemotherapy: refrain from donating sperm PLUSeither be abstinent from heterosexual intercourse as their preferred and usuallifestyle or use contraception and agree to use a male condom plus partner use of anadditional contraceptive

• A female participant is eligible to participate if she is not pregnant orbreastfeeding, and at least one of the following conditions applies: is not a womanof childbearing potential (WOCBP) OR is a WOCBP and using a highly-effectivecontraceptive method during the treatment period and for at least 120 days after thelast dose of pembrolizumab and 180 days after the last dose of chemotherapy (whichever occurs last), AND agrees not to donate eggs (ova, oocytes) to others orfreeze/store for her own use for the purpose of reproduction during this period

• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours for urine or within 72 hours for serum before the first dose of studyintervention

• Has measurable disease per RECIST 1.1 as assessed by the local siteinvestigator/radiologist

• If receiving bisphosphonates or RANK ligand inhibitors, with stable doses for ≥4weeks prior to the date of randomization, the participant may continue receivingthis therapy during the study treatment. If participant needs to initiate theseagents during the screening period, a bone scan to evaluate bone disease should beperformed prior to randomization.

• Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeksprior to the first dose of study intervention and have undetectable HBV viral loadprior to randomization

• Participants with history of Hepatitis C virus (HCV) infection are eligible if HCVviral load is undetectable at screening

Exclusion Criteria:

• Has breast cancer amenable to treatment with curative intent

• Has a history or current evidence of any condition (e.g., transfusion-dependentanemia or thrombocytopenia), therapy, or laboratory abnormality that is specificallycontraindicated per the current locally-approved labeling, that might confound theresults of the study, interfere with the participant's involvement for the fullduration of the study, or is not in the best interest of the participant to beinvolved, in the opinion of the treating investigator

• Has significant cardiac disease, such as: history of myocardial infarction, acutecoronary syndrome, coronary angioplasty/stenting/bypass within the last 6 months,congestive heart failure (CHF) New York Heart association (NYHA) Class II-IV, orhistory of CHF NYHA Class III or IV

• Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolvinginto life-threatening complications, such as lymphangitic lung metastases, bonemarrow replacement, carcinomatous meningitis, significant symptomatic livermetastases, shortness of breath requiring supplemental oxygen, symptomatic pleuraleffusion requiring supplemental oxygen, symptomatic pericardial effusion,symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control

• Has skin only disease

• Has a known germline BRCA mutation (deleterious or suspected deleterious) and hasnot received previous treatment with PARP inhibition. either in the adjuvant ormetastatic setting (where available and not medically contraindicated). Single-agentPARP inhibitor therapy does not count as a line of endocrine therapy.

• Has received prior chemotherapy for locally recurrent inoperable or metastaticbreast cancer

• Has received prior therapy with an anti- programmed cell death 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti- programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitoryT-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40,CD137)

• Has received prior systemic anticancer therapy with other investigational agentswithin 4 weeks prior to randomization

• Has received prior radiotherapy within 2 weeks of start of study intervention orradiation-related toxicities requiring corticosteroids.

• Has received a live or live attenuated vaccine within 30 days prior to the firstdose of study intervention

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior the first dose of study intervention

• Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years with the exception of basal cell carcinoma of theskin, squamous cell carcinoma of the skin, or carcinoma in situ excluding cancer insitu of bladder that have undergone potentially curative therapy

• Has known active central nervous system (CNS) metastases

• Has diagnosed carcinomatous meningitis

• Has severe hypersensitivity to pembrolizumab and/or any of its excipients or has anyhypersensitivity to the planned chemotherapy agent (paclitaxel, nab-paclitaxel,liposomal doxorubicin, or capecitabine) and/or any of their excipients

• Has an active autoimmune disease that has required systemic treatment in past 2years

• Has a history of (noninfectious) pneumonitis/interstitial lung disease that requiredsteroids or has current pneumonitis/interstitial lung disease

• Has an active infection requiring systemic therapy

• Has a known history of Human Immunodeficiency Virus (HIV) infection

• Has a known COVID-19 infection (symptomatic or asymptomatic)

• Has a known history of active tuberculosis (TB)

• Has a known psychiatric or substance abuse disorder including alcohol or drugdependency that would interfere with the participant's ability to cooperate with therequirements of the study

• Is breastfeeding or expecting to conceive or father children within the projectedduration of the study, starting with the screening visit through 180 days (or longeras specified by local institutional guidelines) after the last dose of studytreatment

• Has had an allogenic tissue/solid organ transplant