A Randomized, Phase III Trial to Evaluate the Efficacy and Safety of MK-3475 (Pembrolizumab) as Adjuvant Therapy for Triple Receptor-Negative Breast Cancer With >/= 1 CM Residual Invasive Cancer or Positive Lymph Nodes (ypN+) After Neoadjuvant Chemotherapy


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.

Study Arms

  • Experimental Arm I – Observation
  • Experimental Arm II - Pembrolizumab


  • Patients must have histologically confirmed estrogen receptor (ER)-, progesterone receptor (PR)- and HER2-negative (triple-negative, TNBC) or ER-, PR- weakly positive, and 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. 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; 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; patients must have a complete axillary lymph node dissection after neoadjuvant chemotherapy in the following situations (except for patients participating in the Alliance A11202 trial):
    • 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
    • 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 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
  • English-speaking patients must be willing to participate in the BAHO substudy
  • Patients must have had neoadjuvant chemotherapy followed by surgery; the choice of neoadjuvant chemotherapy is determined by the treating physician; we recommend following the 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 CREATE-X trial) 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 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 or less, 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 screening 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 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; 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
  • 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, insulin, 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.