Summary

This phase III trial compares the effect of continuation of treatment with pembrolizumab (usual approach) to observation only at preventing cancer from coming back in patients with early-stage triple-negative breast cancer (TNBC) who achieved a pathologic complete response after preoperative chemotherapy in combination with pembrolizumab. The usual approach for patients with early-stage TNBC who receive preoperative chemotherapy plus pembrolizumab is to continue to receive pembrolizumab for up to 27 weeks after surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial may help researchers determine if observation is as good as receiving pembrolizumab for 27 weeks after surgery in triple-negative breast cancer patients who achieved a pathologic complete response after preoperative treatment with chemotherapy and pembrolizumab.

Objectives

PRIMARY OBJECTIVES:
I. To evaluate whether observation results in a non-inferior recurrence-free survival (RFS) compared to adjuvant pembrolizumab in early-stage triple-negative breast cancer (TNBC) patients who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy with pembrolizumab.
II. To compare quality of life (QOL) at approximately 27 weeks as assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B) Trial Outcome Index between patients randomized to adjuvant pembrolizumab versus observation. (Quality of Life)
III. To assess the social value of de-escalation of adjuvant breast cancer immunotherapy at approximately 27 weeks and, by modeling, over a lifetime. (Value of Care)

SECONDARY OBJECTIVES:
I. To evaluate whether observation compared to adjuvant pembrolizumab impacts the following:
Ia. RFS by stage at presentation and by receipt of prior anthracycline therapy;
Ib. Adverse event rate: difference in grade 3 or higher adverse event rates overall and grade 3 or higher immune-related adverse events (irAEs) rates;
Ic. Overall survival (OS);
Id. Locoregional recurrence (LRR both isolated LRR as first events and LRR events simultaneous with distant metastasis [DM]);
Ie. RFS, LRR, OS, adverse events, and QOL by age (=< 45, 46-65, and > 65), race, and ethnicity;
If. Adverse events related to receipt of radiotherapy.
II. To assess the value of de-escalation of breast cancer immunotherapy from the payer perspective at approximately 27 weeks and, by modelling, over a lifetime. (Value of Care)
III. To compare patient out-of-pocket costs at approximately 27 weeks between patients randomized to adjuvant pembrolizumab versus observation. (Value of Care)
IV. To compare financial toxicity at approximately 27 weeks between patients randomized to adjuvant pembrolizumab versus observation. (Value of Care)
V. To compare work/productivity impairment at approximately 27 weeks between patients randomized to adjuvant pembrolizumab versus observation. (Value of Care)

EXPLORATORY OBJECTIVES:
I. To describe trajectories of QOL over time among patients randomized to adjuvant pembrolizumab versus (vs.) observation. (Quality of Life)
II. To compare various QOL domains after approximately 27 weeks as assessed by the 5 subscales of the FACT-B Index between patients randomized to adjuvant pembrolizumab versus observation. (Quality of Life)
III. To compare self-reported symptomatic adverse events at approximately 27 weeks assessed by the patient reported outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) between patients randomized to adjuvant pembrolizumab versus observation. (Quality of Life)
IV. To describe trajectories of financial toxicity and work/productivity impairment over time from baseline to approximately 27 weeks among patients randomized to adjuvant pembrolizumab versus observation. (Value of Care)
V. To develop and assess a measure of value from the patient perspective at approximately 27 weeks. (Value of Care)

OUTLINE: Patients are randomized to 1 of 2 arms after completing neoadjuvant chemotherapy in combination with pembrolizumab, followed by definitive breast surgery.

ARM I (PEMBROLIZUMAB): Patients receive pembrolizumab intravenously (IV) on study once every 3 weeks (Q3W) or once every 6 weeks (Q6W) for 27 weeks. Patients also undergo tumor biopsy on study, and collection of blood on study and during follow-up. Patients also undergo mammogram, breast ultrasound or magnetic resonance imaging (MRI) during follow-up.

ARM II (OBSERVATION): Patients undergo observation on study for 27 weeks. Patients also undergo tumor biopsy on study, and collection of blood on study and during follow-up. Patients also undergo mammogram, breast ultrasound or MRI during follow-up.

Patients will be followed every 6 months for 5 years after registration or recurrence. Thereafter, patients will be followed annually for overall survival for a total of 10 years after registration.

Eligibility

1. Age >= 18 years
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
3. Triple Negative Breast Cancer: * Patients with a history of stage T1cN1-2 or T2-4N0-2 breast cancer according to the primary tumor-regional lymph node anatomic staging criteria of the American Joint Committee on Cancer (AJCC), 8th edition as determined by the investigator in radiologic assessment, clinical assessment or both * Patients must have no residual invasive disease in the breast or lymph nodes after 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 Society of 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 is permitted as long as the eligibility criteria are met for both tumors/breasts
4. Patients must have received neoadjuvant chemotherapy in combination with pembrolizumab for a minimum of 6 cycles. All systemic chemotherapy must have been completed preoperatively
5. An interval of no more than 12 weeks between the completion date of the final surgery and the date of randomization * Note: Adjuvant radiation can be given on study. If given, it is encouraged to be given concurrently with pembrolizumab, per investigator discretion. Treatment with adjuvant 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 be completed prior to registration
6. Use of investigational anti-cancer agents must be discontinued at time of registration
7. Adequate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows: * Breast surgery: Total mastectomy or breast-conserving surgery with histologically negative margins, including no ink on tumor for DCIS, at the time of excision ** For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of ductal carcinoma in-situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates DCIS at the line of resection, additional operative procedures may be performed to obtain clear margins. If DCIS is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. 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 biopsy should have been performed at time of surgical evaluation, and if pathologically node positive, the patient is no longer eligible. Isolated tumor cells are considered node-negative ** For a patient with clinically N1 disease at diagnosis (with positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy) additional surgical evaluation of the axilla following preoperative therapy is required *** If they become cN0 (no palpable adenopathy), then a sentinel lymph node biopsy could have been performed at time of surgery (axillary dissection would also be permitted); if the sentinel lymph node biopsy is positive, the patient is no longer eligible ** If sentinel node biopsy performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy. If sentinel node biopsy performed before preoperative therapy was positive, an ALND is required after preoperative therapy ** If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is still required ** If sentinel node evaluation after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required ** Axillary dissection without sentinel node evaluation is permitted as the initial or sole axillary evaluation after preoperative therapy
8. If breast-conserving surgery was performed but patient will not be receiving breast radiation, the patient is not eligible
9. 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 urine pregnancy test done =< 7 days prior to randomization is required
10. Absolute neutrophil count (ANC) >= 1,000/mm^3
11. Platelet Count >= 100,000/mm^3
12. Estimated glomerular filtration rate (eGFR) >= 15 mL/min/1.73m^2
13. Total Bilirubin =<1.5 x upper limit of normal (ULN) * Patients with Gilbert’s disease with a total bilirubin =< 2.5 x ULN and direct bilirubin within normal limits are permitted
14. Aspartate aminotransferase (AST) serum aspartate aminotransferase [SGOT] / alanine aminotransferase (ALT) serum glutamic pyruvic transaminase [SGPT] =< 3 x institutional ULN
15. Patients must be willing to provide tumor tissue from the diagnostic core biopsy. If inadequate tumor tissue is available, patients are still eligible to participate in the trial
16. No stage IV (metastatic) breast cancer
17. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
18. No history of any prior (ipsi- or contralateral) invasive breast cancer. Prior DCIS is allowed
19. No evidence of recurrent disease following preoperative therapy and surgery
20. No known active liver disease, e.g. due to hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatic disorders, or sclerosing cholangitis
21. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
22. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
23. No history of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to pembrolizumab or murine proteins or any components of the product * Note: Prior immune-related adverse events (irAEs) are allowed if they resolved and the patient tolerated subsequent therapy without requiring chronic steroids for the irAE
24. No medical conditions that require chronic systemic steroids (>10 mg prednisone daily or equivalent) or any other form of immunosuppressive medications and has required such therapy in the last two 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
25. Patients who are unable or unwilling to comply with the requirements of the protocol per investigator assessment are not eligible