Testing MK-3475 (Pembrolizumab) as Adjuvant Therapy for Triple Receptor-Negative Breast Cancer
Testing MK-3475 (Pembrolizumab) as Adjuvant Therapy for Triple Receptor-Negative Breast Cancer
This randomized phase III trial studies how well pembrolizumab works in treating patients
 with triple-negative breast cancer. 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.
PRIMARY OBJECTIVE:

 I. To compare invasive disease-free survival (IDFS) of patients with triple-negative (TNBC)
 or low estrogen receptor (ER)-positive and/or HER2 borderline breast cancer who have >= 1 cm
 residual invasive breast cancer and/or positive lymph nodes (ypN1mi, ypN1, ypN2, ypN3) after
 neoadjuvant chemotherapy randomized to receive 1 year of MK-3475 (pembrolizumab) adjuvant
 therapy compared to no MK-3475 (pembrolizumab), in both the entire study population and also
 in the PD-L1 positive subset.

 SECONDARY OBJECTIVES:

 I. To compare the effects of MK-3475 (pembrolizumab) on overall survival (OS) and distant
 recurrence-free survival (DRFS) between the two randomized arms for the PD-L1 positive
 patients and then all patients.

 II. To assess the toxicity and tolerability of MK-3475 (pembrolizumab) in this patient
 population with or without radiation therapy.

 BEHAVIORAL AND HEALTH OUTCOMES (BAHO) STUDY OBJECTIVES:

 I. To examine the association between biomarkers of inflammation and quality of life and
 patient reported outcomes between the two groups during and at the end of therapy.

 II. To examine the long-term and late effects of treatment on patient-reported outcomes.

 ADDITIONAL OBJECTIVE:

 I. To collect tissue and whole blood for processing and banking in anticipation of future
 correlative studies in this patient population.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I (OBSERVATION): Patients receive no treatment but are monitored at standard clinical
 intervals during first year after randomization. Patients are examined every 12 weeks for 1
 year, and every 6 months for 4 years, then annually for 5 years.

 ARM II (PEMBROLIZUMAB): Patients receive pembrolizumab intravenously (IV) over 30 minutes on
 days 1 and 22. Cycles repeat every 42 days for 52 weeks in the absence of disease progression
 or unacceptable toxicity.

 All patients may undergo radiation therapy within 12 weeks of last breast cancer operation or
 after treatment.

 After completion of study treatment, patients are followed up every 6 months for 5 years,
 then annually thereafter until 10 years from treatment randomization.
Inclusion Criteria:

 -  STEP 1 REGISTRATION

 -  Patients must have histologically confirmed estrogen receptor (ER)-, progesterone
 receptor (PR)- and HER2-negative (triple-negative, TNBC) or ER-, PR- weakly positive
 and/or HER2- equivocal status and must not have received and not be planning to
 receive adjuvant anti-HER2 or endocrine therapies after completion of neoadjuvant
 chemotherapy; patients who are HER2-positive by American Society of Clinical Oncology
 (ASCO) College of American Pathologists (CAP) guidelines are ineligible; HER2-negative
 and HER2-equivocal cases as per ASCO CAP guidelines that do not receive HER2-targeted
 therapy are eligible; patients with weakly ER or PR positive disease, defined as ER
 and/or PR less than or equal to (=<) 5% by immunohistochemistry, are eligible if the
 treating physician considers the patient not eligible for adjuvant endocrine therapy;
 residual disease must be >= 1 cm in greatest dimension, and/or have positive lymph
 nodes (ypN1mi, ypN1, ypN2, ypN3) observed on pathologic exam

 -  NOTE: If the ER and/or HER2 results are discordant between the initial,
 pre-chemotherapy, and post-chemotherapy surgical tissue, the receptor status of
 the residual disease has to be used to determine eligibility.
 Immunohistochemistry (IHC)-positive isolated tumor cells in the lymph node (N0
 [i+]) are not considered node-positive and these patients also must have >= 1 cm
 residual invasive cancer in the breast to be eligible.

 -  Patients must not have metastatic disease (i.e., must be clinically M0 or Mx; systemic
 staging studies with imaging should follow routine practice as per National
 Comprehensive Cancer Network [NCCN] and ASCO guidelines); patients must not have
 locally recurrent disease

 -  It is preferred that axillary lymph node sampling is performed after completion of
 neoadjuvant chemotherapy to allow more accurate assessment of pathologic response;
 complete axillary lymph node dissection (ALND) after neoadjuvant chemotherapy is
 recommended in the following situations:

 -  Patients had documented pathologic involvement of the axillary nodes (fine needle
 aspiration [FNA] or core biopsy) before neoadjuvant chemotherapy and had sentinel
 node biopsy after neoadjuvant chemotherapy with positive sentinel node(s)

 -  Patient had documented pathologic involvement of the axillary nodes (FNA or core
 biopsy) before neoadjuvant chemotherapy and had only 1 sentinel lymph node
 removed after neoadjuvant chemotherapy

 -  Except for (i) patients participating in the Alliance A11202 trial) or (ii)
 if the treating surgeon determines that a complete ALND is not in the best
 interest of the patient

 -  NOTE: Patients who undergo sentinel node biopsy before starting neoadjuvant
 treatment and do not undergo post neoadjuvant assessment of the axillary
 nodes or who have negative axillary nodes on post neoadjuvant assessment
 must have >= 1 cm residual invasive cancer in the breast after completion of
 neoadjuvant chemotherapy

 -  Patients must have a minimum of five, available unstained formalin-fixed
 paraffin-embedded (FFPE) slides (4-5 micron thickness) from the residual
 (post-neoadjuvant) invasive tumor in primary site or lymph node; (these will be
 submitted to a central laboratory to determine PD-L1 expression); the tumor tissue
 must be adequate for PD-L1 testing, which typically requires a minimum of 100 cancer
 cells per slide; local PD-L1 results, even if available, will not substitute for
 central testing

 -  NOTE: Initial order for specimen kits should be placed at least two weeks prior
 to registering the first patient at each site

 -  Patients must be offered the opportunity to participate in specimen banking

 -  The BAHO substudy was permanently closed to accrual on June 23, 2020, and willingness
 of English-speaking patients to participate in the BAHO substudy is no longer
 applicable

 -  Patients must have had neoadjuvant chemotherapy followed by surgery; the choice of
 neoadjuvant chemotherapy is determined by the treating physician; we recommend
 following the National Comprehensive Cancer Network (NCCN) treatment guidelines for
 TNBC; patients who cannot complete all planned treatment cycles for any reason are
 considered high risk and therefore are eligible for the study if they have residual
 disease; patients must have resolution of adverse event(s) of the most recent prior
 chemotherapy to grade 1 or less, except alopecia and =< grade 2 neuropathy which are
 allowed

 -  Patients may receive post-operative (adjuvant) chemotherapy for up to 24 weeks of
 duration (e.g. 8 cycles of capecitabine as in the Capecitabine for Residual Cancer as
 Adjuvant Therapy (CREATE-X) trial; the 24-week duration does not include treatment
 delays) after completion of surgery at the discretion of the treating physician;
 co-enrollment to EA1131 is allowed, provided that patients complete or discontinue
 adjuvant chemotherapy prior to step 1 registration; at the time of step 1
 registration, patients must have resolution of adverse event(s) of the most recent
 prior chemotherapy to =< grade 1, except alopecia and =< grade 2 neuropathy which are
 allowed; patients that have received adjuvant chemotherapy (including via
 co-enrollment to EA1131) must be registered to step 1 within 35 days after final dose
 of adjuvant chemotherapy

 -  Patients must have completed their final breast surgery (rendering them free from
 disease) with clear resection margins for invasive cancer and DCIS within the
 following timelines:

 -  90 days prior to step 1 screening registration for patients not receiving
 post-operative (adjuvant) chemotherapy OR

 -  270 days prior to step 1 screening registration for patients who have received
 post-operative (adjuvant) chemotherapy Positive margins are allowed only if the
 surgical team of the patient deems further resection impossible

 -  Patients for whom radiation therapy (RT) to the affected breast or chest wall and
 regional nodal areas is clinically indicated as per NCCN treatment guidelines, should
 receive routine RT after randomization when possible, and receive MK-3475
 (pembrolizumab) concurrent with RT, if randomized to the experimental arm; however,
 routine RT administered, or initiated, prior to registration is also allowed; MK-3475
 (pembrolizumab) may be added to ongoing radiation, or started after its completion, if
 randomized to the experimental arm, provided there are no > grade 1 radiation-related
 skin toxicities and provided that no radiosensitizing chemotherapy is being
 administered; co-enrollment in the Alliance A221505 (NCT03414970) and A011202
 (NCT01901094) trials or in the NSABP-B51 (NCT01872975) trial is allowed, but patients
 must not be planning to receive radiation therapy given on these trials concurrently
 with MK-3475 (pembrolizumab) treatment on S1418/BR006; whether or not patient will
 receive RT and the extent of intended RT must be specified at time of registration;
 NOTE: Patients who receive post-operative chemotherapy may receive radiation therapy
 before or after the chemotherapy; a short course of reduced dose chemotherapy or other
 agents concomitant with radiation for radiation sensitization is not considered to be
 adjuvant chemotherapy

 -  Patients must not have had prior immunotherapy with anti-PD-L1, anti-PD-1, anti-CTLA4
 or similar drugs; patients must not be planning to receive any of the prohibited
 therapies during the screening or treatment phases of the study

 -  Patients must not be planning to receive concomitantly other biologic therapy,
 hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except
 radiation therapy while receiving treatment on this protocol; however, patients
 receiving extended adjuvant endocrine therapy for an earlier ER positive breast cancer
 treated with curative intent and without recurrence for at least 5 years may continue
 with their endocrine therapy; elective surgery or surgery that is not related to
 cancer therapy is allowed, at the discretion of the treating investigator

 -  Patients must have Zubrod performance status =< 2

 -  Patients must not have a history of (non-infectious) pneumonitis that required
 steroids or evidence of active pneumonitis within 2 years prior to registration

 -  Patients must not have active autoimmune disease that has required systemic treatment
 in past 2 years (i.e., with use of disease modifying agents, corticosteroids or
 immunosuppressive drugs); replacement therapy (e.g., thyroxine for pre-existing
 hypothyroidism, insulin for type I diabetes mellitus, or physiologic corticosteroid
 replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
 form of systemic treatment

 -  Patients must not have received live vaccines within 30 days prior to registration;
 examples of live vaccines include, but are not limited to, the following: measles,
 mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin
 (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are
 generally killed virus vaccines and are allowed; however, intranasal influenza
 vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

 -  Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
 infection prior to registration; patients who have completed curative therapy for HCV
 are eligible; patients with known human immunodeficiency virus (HIV) infection are
 eligible if they meet each of the following 3 criteria:

 -  CD4 counts >= 350 mm^3

 -  Serum HIV viral load of < 25,000 IU/ml and

 -  Treated on a stable antiretroviral regimen

 -  No other prior invasive malignancy is allowed except for the following: adequately
 treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer; stage
 I or II invasive cancer treated with a curative intent without evidence of disease
 recurrence for at least five years

 -  Patients must have complete history and physical examination within 28 days prior to
 registration

 -  Patients must be informed of the investigational nature of this study and must sign
 and give written informed consent for this protocol in accordance with institutional
 and federal guidelines

 -  As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
 treating institution's identity is provided in order to ensure that the current
 (within 365 days) date of institutional review board approval for this study has been
 entered in the system

 -  STEP 2 REGISTRATION

 -  Patients must not be registered to step 2 until receiving confirmation from the
 Southwest Oncology Group (SWOG) Statistical and Data Management Center that the
 patient's tissue specimen was adequate for PD-L1 testing; patients must be registered
 within 14 days of receiving the e-mail notification confirming submission was
 evaluable for PD-L1 status

 -  Absolute neutrophil count (ANC) >= 1,500 microliter (mcL) (obtained within 28 days
 prior to step 2 registration)

 -  Platelets >= 100,000/mcL (obtained within 28 days prior to step 2 registration)

 -  Hemoglobin >= 9 g/dL (obtained within 28 days prior to step 2 registration)

 -  A serum thyroid-stimulating hormone (TSH) and/or free T4 must be obtained within 28
 days prior to step 2 registration to obtain a baseline value

 -  Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except Gilbert's
 syndrome, who must have a total bilirubin < 3.0 mg/dL) (obtained within 28 days prior
 to step 2 registration)

 -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
 IULN (obtained within 28 days prior to step 2 registration)

 -  Alkaline phosphatase =< 2.5 x IULN (obtained within 28 days prior to step 2
 registration)

 -  Serum creatinine =< IULN OR measured or calculated creatinine clearance >= 60 mL/min
 (obtained within 28 days prior to step 2 registration)

 -  Women of childbearing potential must have a negative urine or serum pregnancy test
 within 28 day prior to registration; women/men of reproductive potential must have
 agreed to use an effective contraceptive method for the course of the study through
 120 days after the last dose of study medication; should a woman become pregnant or
 suspect she is pregnant while she or her partner is participating in this study, she
 should inform her treating physician immediately; a woman is considered to be of
 "reproductive potential" if she has had menses at any time in the preceding 12
 consecutive months; in addition to routine contraceptive methods, "effective
 contraception" also includes heterosexual celibacy and surgery intended to prevent
 pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
 bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any
 point a previously celibate patient chooses to become heterosexually active during the
 time period for use of contraceptive measures outlined in the protocol, he/she is
 responsible for beginning contraceptive measures; patients must not be pregnant or
 nursing; women of childbearing potential must plan to have a urine or serum pregnancy
 test within 72 hours prior to receiving the first dose of study medication; if the
 urine test is positive or cannot be confirmed as negative, a negative serum pregnancy
 test will be required

 -  Patients must not have an active infection requiring systemic therapy at the time of
 starting therapy

 -  Site must verify that there is no known change in the step 1 eligibility since initial
 registration