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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Double-Blind, Phase III Study of Pembrolizumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy for the Treatment of High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Breast Cancer (KEYNOTE-756)

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: Pembrolizumab (K)
* Drug: Placebo (P)
* Drug: Paclitaxel (X)
* Drug: Doxorubicin (A)
* Drug: Epirubicin (E)
* Drug: Cyclophosphamide (C)
* Drug: Endocrine therapy
* Radiation: Radiation therapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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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 (FFPE) tumor tissue sample or slides that were obtained greater than 60 days prior to the date that the documented informed consent was obtained. 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. 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. 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 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 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab+Chemotherapy (KX/KA[E]C)<br>In the neoadjuvant setting, participants receive pembrolizumab (K) 200 mg via intravenous (IV) infusion once every 3 weeks (Q3W) + paclitaxel (X) 80 mg/m^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by pembrolizumab 200 mg via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m^2 or 100 mg/m^2) via IV infusion either in Q2W or Q3W + cyclophosphamide (C) 600 mg/m^2 via IV infusion either in Q2W or Q3W for 4 cycles (Treatment 2). At no more than 6 weeks after last cycle of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive pembrolizumab 200 mg via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long. | Biological: Pembrolizumab (K)<br>* IV infusion Q3W<br>* Other names: KEYTRUDA®;Drug: Paclitaxel (X)<br>* IV infusion QW<br>* Other names: TAXOL®;Drug: Doxorubicin (A)<br>* IV infusion either in Q2W or Q3W<br>* Other names: ADRIAMYCIN®;Drug: Epirubicin (E)<br>* IV infusion either in Q2W or Q3W<br>* Other names: ELLENCE®;Drug: Cyclophosphamide (C)<br>* IV infusion either in Q2W or Q3W<br>* Other names: CYTOXAN®;Drug: Endocrine therapy<br>* Variable endocrine therapy for up 10 years<br>Radiation: Radiation therapy<br>* Variable radiation therapy per local standard of care<br>Procedure: Surgery<br>* Surgery for breast cancer<br>|
| Placebo Comparator: Placebo+Chemotherapy (PX/PA[E]C)<br>In the neoadjuvant setting, participants receive placebo (P; normal saline or dextrose) via IV infusion Q3W + paclitaxel (X) 80 mg/m^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by placebo via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m^2 or 100 mg/m^2) via IV infusion either in Q2W or Q3W + cyclophosphamide (C) 600 mg/m^2 via IV infusion either in Q2W or Q3W for 4 cycles (Treatment 2). At no more than 6 weeks after last cycle of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive placebo via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long. | Drug: Placebo (P)<br>* Normal saline or dextrose IV infusion Q3W<br>Drug: Paclitaxel (X)<br>* IV infusion QW<br>* Other names: TAXOL®;Drug: Doxorubicin (A)<br>* IV infusion either in Q2W or Q3W<br>* Other names: ADRIAMYCIN®;Drug: Epirubicin (E)<br>* IV infusion either in Q2W or Q3W<br>* Other names: ELLENCE®;Drug: Cyclophosphamide (C)<br>* IV infusion either in Q2W or Q3W<br>* Other names: CYTOXAN®;Radiation: Radiation therapy<br>* Variable radiation therapy per local standard of care<br>Procedure: Surgery<br>* Surgery for breast cancer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 | The pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by American Joint Committee on Cancer (AJCC) staging criteria (8th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pathological Complete Response (pCR) using the definition of (ypT0/Tis ypN0) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies. | Up to approximately 7 months (Time of surgery) | 
| Event-Free Survival (EFS) | EFS is defined as the time from randomization to disease progression that: precludes surgery, results in a local or distant recurrence, results in a second primary malignancy, or death due to any cause whichever occurs first. The EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator will be presented. | Up to approximately 12 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from date of randomization to date of death due to any cause. The OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies will be presented. | Up to approximately 12 years | 
| pCR Rate Using the Definition of ypT0ypN0 | pCR rate (ypT0ypN0) is defined as the percentage of participants without residual invasive or in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy by AJCC staging criteria (8th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pCR using the definition of (ypT0ypN0) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies. | Up to approximately 7 months (Time of surgery) | 
| pCR Rate Using the Definition of ypT0/Tis | pCR rate (ypT0/Tis) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen (independent of lymph node involvement) after completion of neoadjuvant systemic therapy by AJCC staging criteria (8th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pCR using the definition of ypT0/Tis will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies. | Up to approximately 7 months (Time of surgery) | 
| pCR Rate Using the Definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in Participants With a Combined Positive Score [CPS] ≥1 | pCR rates were calculated using the definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 after completion of neoadjuvant systemic therapy by AJCC staging criteria (8th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pCR using the three definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in participants with a CPS ≥1 (with a positive Programmed Cell Death-Ligand 1 [PD-L1] tumor status) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies. | Up to approximately 7 months (Time of surgery) | 
| EFS in Participants With a CPS ≥1 | EFS is defined as the time from randomization to disease progression that: precludes surgery, results in a local or distant recurrence, results in a second primary malignancy, or death due to any cause whichever occurs first. The EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator for participants with a CPS ≥1 will be presented. | Up to approximately 12 years | 
| OS in Participants With a CPS ≥1 | OS is defined as the time from date of randomization to date of death due to any cause. The OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies for participants with a CPS ≥1 will be presented. | Up to approximately 12 years | 
| Number of Participants Experiencing an Adverse Event (AE) | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE while receiving pembrolizumab or placebo (including 1 month of safety follow up) will be presented. | Up to approximately 15 months | 
| Number of Participants Experiencing a Serious Adverse Event (SAE) | An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, Is life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity or Is a congenital anomaly/birth defect. The number of participants who experience an SAE while receiving pembrolizumab or placebo (including 3 months of safety follow up) will be presented. | Up to approximately 17 months | 
| Number of Participants Experiencing an Immune-related AE (irAE) | Some AEs that may occur in this study that are known to be related to pembrolizumab immunotherapy treatment and may include: pneumonitis, diarrhea/colitis, aspartate aminotransferase/alanine aminotransferase (AST/ALT) elevation or increased bilirubin, Type 1 diabetes mellitus or hyperglycemia, hypophysitis, hyperthyroidism, hypothyroidism, nephritis and renal dysfunction, and myocarditis. The number of participants who experience an irAE while receiving pembrolizumab or placebo (including 1 month of safety follow up) will be presented. | Up to approximately 15 months | 
| Number of Participants who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment (pembrolizumab or placebo) due to an AE will be presented. | Up to approximately 14 months | 
| Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core 30 (QLQ-C30) Score | The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Individual responses for each of 28 items are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome, and responses for each of 2 items (overall health and overall quality of life) are given on a 7-point scale (1=Very poor to 7=Excellent), with a higher score indicating a better outcome. The change from Baseline to end of treatment (up to Cycle 4 Day 1) in EORTC-QLQ-C30 scores for participants will be presented. | Baseline (Cycle 1 Day 1 in Treatment 1) and Cycles 1 and 4 Day 1 in Treatment 2 (Up to approximately 5 months) Each cycle is 21 days. | 
| Change from Baseline in EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) Score | The EORTC QLQ-BR23 is a 23-item questionnaire developed to assess the quality of life in women with breast cancer. Responses for each item are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The change from Baseline to end of treatment (up to Cycle 4 Day 1) in EORTC QLQ-BR23 score for participants will be presented. | Baseline (Cycle 1 Day 1 in Treatment 1) and Cycles 1 and 4 Day 1 in Treatment 2 (Up to approximately 5 months) Each cycle is 21 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD1, PD-1, PDL1, PD-L1