Pembrolizumab vs. Observation in People With Triple-negative Breast Cancer Who Had a Pathologic Complete Response After Chemotherapy Plus Pembrolizumab

Inclusion Criteria:

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

• Triple Negative Breast Cancer:

• Patients with a history of stage T1cN1-2 or T2-4N0-2 breast cancer according tothe primary tumor-regional lymph node anatomic staging criteria of the AmericanJoint Committee on Cancer (AJCC), 8th edition as determined by the investigatorin radiologic assessment, clinical assessment or both

• Patients must have no residual invasive disease in the breast or lymph nodesafter the completion of neoadjuvant therapy. Residual ductal carcinoma in situ (DCIS) is allowed. Isolated tumor cells are considered node-negative

• Estrogen (ER) and progesterone (PR) =< 10%; HER2-negative by American Societyof Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH])

• If invasive disease was present in both breasts, participation in the study ispermitted as long as the eligibility criteria are met for both tumors/breasts

• Patients must have received neoadjuvant chemotherapy in combination withpembrolizumab for a minimum of 6 cycles. All systemic chemotherapy and ICI therapyshould have been completed preoperatively

• An interval of no more than 12 weeks between the completion date of the finalsurgery and the date of randomization

• Note: Adjuvant radiation can be given on study. If given, it is encouraged to begiven concurrently with pembrolizumab, per investigator discretion. Treatment withadjuvant pembrolizumab is strongly discouraged prior to participation in this trial,but if administered (e.g., if patients are awaiting pathology results),pembrolizumab may be administered for up to 6 weeks post-surgery and must becompleted prior to registration

• Use of investigational anti-cancer agents must be discontinued at time ofregistration

• Adequate excision: Surgical removal of all clinically evident disease in the breastand lymph nodes as follows:

• Breast surgery: Total mastectomy or breast-conserving surgery withhistologically negative margins, including no ink on tumor for DCIS, at thetime of excision ** For patients who undergo breast-conserving surgery, the margins of theresected specimen must be histologically free of ductal carcinoma in-situ (DCIS) as determined by the local pathologist. If pathologic examinationdemonstrates DCIS at the line of resection, additional operative procedures maybe performed to obtain clear margins. If DCIS is still present at the resectedmargin after re-excision(s), the patient must undergo total mastectomy to beeligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection

• Lymph node surgery:

• For a patient with clinically N0 disease, a sentinel lymph node biopsyshould have been performed at time of surgical evaluation, and ifpathologically node positive, the patient is no longer eligible. Isolatedtumor cells are considered node-negative

• For a patient with clinically N1 disease at diagnosis (with positiveresults from a fine-needle aspiration, core biopsy, or sentinel nodebiopsy performed prior to preoperative therapy) additional surgicalevaluation of the axilla following preoperative therapy is required *** If they become cN0 (no palpable adenopathy), then a sentinel lymphnode biopsy could have been performed at time of surgery (axillarydissection would also be permitted); if the sentinel lymph node biopsy ispositive, the patient is no longer eligible

• If sentinel node biopsy performed before preoperative therapy wasnegative, no additional surgical evaluation of the axilla is requiredafter preoperative therapy. If sentinel node biopsy performed beforepreoperative therapy was positive, an ALND is required after preoperativetherapy

• If the only sentinel node identified by isotope scan is in the internalmammary chain, surgical evaluation of the axilla is still required

• If sentinel node evaluation after preoperative therapy is negative, nofurther additional surgical evaluation of the axilla is required

• Axillary dissection without sentinel node evaluation is permitted as theinitial or sole axillary evaluation after preoperative therapy

• If breast-conserving surgery was performed but patient will not be receiving breastradiation, the patient is not eligible

• Not pregnant and not nursing, because this study involves an agent whose genotoxic,mutagenic and teratogenic effects on the developing fetus and newborn are unknown.Therefore, for women of childbearing potential only, a negative serum or urinepregnancy test done =< 7 days prior to randomization is required

• Absolute neutrophil count (ANC) >= 1,000/mm^3

• Platelet Count >= 100,000/mm^3

• Estimated glomerular filtration rate (eGFR) >= 15 mL/min/1.73m^2

• Total Bilirubin =<1.5 x upper limit of normal (ULN)

• Patients with Gilbert's disease with a total bilirubin =< 2.5 x ULN and directbilirubin within normal limits are permitted

• Aspartate aminotransferase (AST) serum aspartate aminotransferase [SGOT] / alanineaminotransferase (ALT) serum glutamic pyruvic transaminase [SGPT] =< 3 xinstitutional ULN

• Patients must be willing to provide tumor tissue from the diagnostic core biopsy. Ifinadequate tumor tissue is available, patients are still eligible to participate inthe trial

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months prior to registration areeligible for this trial

Exclusion Criteria:

• No stage IV (metastatic) breast cancer

• No history of any prior (ipsi- or contralateral) invasive breast cancer. Prior DCISis allowed

• No evidence of recurrent disease following preoperative therapy and surgery

• No known active liver disease, e.g. due to hepatitis B virus (HBV), hepatitis Cvirus (HCV), autoimmune hepatic disorders, or sclerosing cholangitis

• No history of intolerance, including Grade 3 or 4 infusion reaction orhypersensitivity to pembrolizumab or murine proteins or any components of theproduct

• Note: Prior immune-related adverse events (irAEs) are allowed if they resolved andthe patient tolerated subsequent therapy without requiring chronic steroids for theirAE

• No medical conditions that require chronic systemic steroids (>10 mg prednisonedaily or equivalent) or any other form of immunosuppressive medications and hasrequired such therapy in the last two years. Replacement therapy (e.g. thyroxine,insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic therapy

• Patients who are unable or unwilling to comply with the requirements of the protocolper investigator assessment are not eligible