Study of Pembrolizumab (MK-3475) Versus Placebo in Combination With Neoadjuvant Chemotherapy & Adjuvant Endocrine Therapy in the Treatment of Early-Stage Estrogen Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Breast Cancer (MK-3475-756/KEYNOTE-756)

  • End date
    Jan 24, 2031
  • participants needed
  • sponsor
    Merck Sharp & Dohme Corp.
Updated on 22 September 2021
growth factor
endocrine therapy
hormone therapy
epidermal growth factor receptor
cancer treatment
progesterone receptor
epidermal growth factor
estrogen receptor
inflammatory breast cancer
core needle biopsy


The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475) versus placebo in combination with neoadjuvant (pre-surgery) chemotherapy and adjuvant (post-surgery) endocrine therapy in the treatment of adults who have high-risk early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer.

The primary study hypotheses are: 1) pembrolizumab is superior to placebo, both in combination with the protocol-specified neoadjuvant anticancer therapy, as assessed by pathological Complete Response (pCR) rate defined by the local pathologist, and 2) pembrolizumab is superior to placebo (both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies) as assessed by Event-Free Survival (EFS) as determined by the investigator. The study is considered to have met its primary objective if pembrolizumab is superior to placebo with respect to either pCR (ypT0/Tis ypN0) or EFS.


Study participants will receive 8 cycles of neoadjuvant study treatment and then will undergo surgery for their breast cancer. After surgery, participants will receive 9 cycles of study treatment and up to 10 years of variable endocrine therapy. Each cycle is 21 days long.

Condition Breast Cancer, Breast Cancer Diagnosis, breast carcinoma, cancer, breast
Treatment radiation therapy, Surgery, Endocrine Therapy, Pembrolizumab (K), Placebo (P), Paclitaxel (X), Doxorubicin hydrochloride (A), Epirubicin (E), Cyclophosphamide (C), Doxorubicin (A)
Clinical Study IdentifierNCT03725059
SponsorMerck Sharp & Dohme Corp.
Last Modified on22 September 2021


Yes No Not Sure

Inclusion Criteria

Has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size 2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2. Note: Inflammatory breast cancer is allowed
Has centrally confirmed ER+/HER2-, Grade 3 breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines
Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, grade, and PD-L1 status
Note: Sponsor agreement is required for formalin-fixed paraffin-embedded
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment
Male participants must agree to use contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period
(FFPE) tumor tissue sample or slides that were obtained greater than 60 days
Female participants must agree to use effective contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo
prior to the date that the documented informed consent was obtained
Has adequate organ function

Exclusion Criteria

Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis
Has breast cancer with lobular histology
Has bilateral invasive breast cancer
Has metastatic (Stage IV) breast cancer
Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast)
Has any of the following clinical lymph node staging per current American Joint Committee on Cancer (AJCC) staging criteria for breast cancer staging based on radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c
Has ER-, progesterone receptor positive breast cancer
Has undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or has undergone sentinel lymph node biopsy prior to study treatment
Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years
Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, ductal breast carcinoma in situ, or cervical carcinoma
in situ that has undergone potentially curative therapy are not excluded
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
Has a known history of active tuberculosis (Bacillus tuberculosis)
Has an active infection requiring systemic therapy
Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening
Has a known history of human immunodeficiency virus (HIV) infection
Has a known history of hepatitis B or known active hepatitis C virus infection
Has received prior treatment for breast cancer
Has other significant cardiac disease, such as: 1) History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months. or 2) Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV
Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137)
Has received a live vaccine within 30 days prior to the first dose of study treatment
Has severe hypersensitivity (Grade 3) to any of the components or excipients used in the study treatments
Is/was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks (12 months for an investigational agent or device with anticancer or antiproliferative properties) prior to the first dose of study treatment
Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment
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