Testing MK-3475 (Pembrolizumab) as Adjuvant Therapy for Triple Receptor-Negative Breast Cancer

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 be >= 18 years of age

   - 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