NCT03036488 · CITED IN SOURCE DOCUMENTS

Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2025-10-29

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants who have triple negative breast cancer (TNBC). After a screening phase of approximately 28 days, each participant will receive neoadjuvant study treatment (Pembrolizumab + Chemotherapy OR Placebo + Chemotherapy) based on the randomization schedule for approximately 24 weeks (8 cycles). Each participant will then undergo definitive surgery 3-6 weeks after conclusion of the last cycle of the neoadjuvant study treatment. After definitive surgery, each participant will receive adjuvant study treatment (Pembrolizumab OR Placebo) for approximately 27 weeks (9 cycles). Following adjuvant study treatment, each participant will be monitored for safety, survival and disease recurrence. The primary study hypothesis is that pembrolizumab is superior to placebo, in combination with chemotherapy, as measured by the rate of Pathological Complete Response (pCR) and/or Event-free Survival (EFS), in participants with locally advanced TNBC.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

eligibility Criteria: Inclusion Criteria: * Has newly diagnosed, locally advanced, centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. * Has previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current American Joint Committee of Cancer (AJCC) staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment: * T1c, N1-N2 * T2, N0-N2 * T3, N0-N2 * T4a-d, N0-N2 * Provides a core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory. * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation. * Demonstrates adequate organ function. * Males and female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and 6 months after the last dose of study treatment for participants who did not. Exclusion Criteria: * Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. * Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months. * Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death - ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen-4 \[CTLA-4\], OX-40, CD137 \[tumor necrosis factor receptor superfamily member 9 (TNFRSF9)\]) or has previously participated in a pembrolizumab (MK-3475) clinical study. * Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 4 weeks of the first dose of treatment in this current study. * Has received a live vaccine within 30 days of the first dose of study treatment. * Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e., dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. * Has a known history of Human Immunodeficiency Virus (HIV). * Has known active Hepatitis B or Hepatitis C. * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. * Has an active infection requiring systemic therapy. * Has significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV. * Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for participants who have not. * Has a known hypersensitivity to the components of the study treatment or its analogs. * Has a known history of active tuberculosis (TB, Bacillus Tuberculosis).
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.
intervention Names
Biological: Pembrolizumab
Drug: Carboplatin
Drug: Paclitaxel
Drug: Doxorubicin
Drug: Epirubicin
Drug: Cyclophosphamide
Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim
label
Pembrolizumab + Chemotherapy
type
EXPERIMENTAL
description
Participants receive placebo (normal saline solution) Q3W + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by placebo + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of placebo Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.
intervention Names
Drug: Carboplatin
Drug: Paclitaxel
Drug: Doxorubicin
Drug: Epirubicin
Drug: Cyclophosphamide
Drug: Placebo
Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim
label
Placebo + Chemotherapy
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Pembrolizumab + Chemotherapy
description
On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; intravenous (IV) infusion.
name
Pembrolizumab
other Names
MK-3475
KEYTRUDA®
type
BIOLOGICAL
arm Group Labels
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy
description
On Day 1 of Cycles 1-4 of the neoadjuvant phase of the study OR on Days 1, 8, 15 of Cycles 1-4 of the neoadjuvant phase of the study; IV infusion.
name
Carboplatin
other Names
PARAPLATIN®
type
DRUG
arm Group Labels
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy
description
On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.
name
Paclitaxel
other Names
TAXOL®
type
DRUG
arm Group Labels
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy
description
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.
name
Doxorubicin
other Names
ADRIAMYCIN®
type
DRUG
arm Group Labels
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy
description
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.
name
Epirubicin
other Names
ELLENCE®
type
DRUG
arm Group Labels
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy
description
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.
name
Cyclophosphamide
other Names
CYTOXAN®
type
DRUG
arm Group Labels
Placebo + Chemotherapy
description
normal saline solution or dextrose: On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; IV infusion
name
Placebo
type
DRUG
arm Group Labels
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy
description
For prevention of neutropenia, filgrastim 5 μg/kg/day via subcutaneous (SC) injection administered per standard of care after chemotherapy OR pegfilgastrim 100 µg/kg (individualized) or 6 mg (general approach) via SC injection administered per standard of care.
name
Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim
other Names
NEUPOGEN®
NEULASTA®
type
BIOLOGICAL

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: QUADRUPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 1174
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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 current American Joint Committee on Cancer (AJCC) staging criteria assessed by the local pathologist at the time of definitive surgery.
measure
Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery
time Frame
Up to approximately 27-30 weeks
description
EFS is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause.
measure
Event-free Survival (EFS) as assessed by Investigator
time Frame
Up to approximately 8 years

secondary Outcomes

description
pCR rate (ypT0 ypN0) is defined as the percentage of participants without residual invasive and in situ 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 current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in all participants and in participants with tumors expressing Programmed Death-Ligand 1 (PD-L1).
measure
pCR rate using an alternative definition, ypT0 ypN0 (i.e., no invasive or noninvasive residual in breast or nodes) at the time of definitive surgery
time Frame
Up to approximately 27-30 weeks
description
pCR rate (ypT0/Tis) is defined as the percentage of participants without invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in participants with tumors expressing PD-L1.
measure
pCR rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery
time Frame
Up to approximately 27-30 weeks
description
EFS is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause.
measure
EFS in participants with tumors expressing PD-L1
time Frame
Up to approximately 8 years
description
pCR rate (ypT0/Tis) is defined as the percentage of participants without invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in all participants and in participants with tumors expressing PD-L1.
measure
pCR rate using an alternative definition, ypT0/Tis (i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) at the time of definitive surgery
time Frame
Up to approximately 27-30 weeks
description
OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis will be censored at the date of the last follow-up.
measure
Overall survival (OS)
time Frame
Up to approximately 8 years
description
An AE is defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE.
measure
Percentage of participants who experience an adverse event (AE)
time Frame
Up to approximately 61 weeks
description
An AE is defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE.
measure
Percentage of participants who discontinue study treatment due to an AE
time Frame
Up to approximately 57 weeks
description
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Individual responses are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The EORTC-QLQ-C30 score will be presented for all participants and for participants with tumors expressing PD-L1.
measure
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) score
time Frame
Up to approximately 27-30 weeks
description
The EORTC-QLQ-BR23 is a 23-item questionnaire developed to assess the quality of life of breast cancer patients. Individual responses are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The EORTC-QLQ-BR23 score will be presented for all participants and for participants with tumors expressing PD-L1.
measure
EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) score
time Frame
Up to approximately 27-30 weeks

Full study description

brief Summary: The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants who have triple negative breast cancer (TNBC). After a screening phase of approximately 28 days, each participant will receive neoadjuvant study treatment (Pembrolizumab + Chemotherapy OR Placebo + Chemotherapy) based on the randomization schedule for approximately 24 weeks (8 cycles). Each participant will then undergo definitive surgery 3-6 weeks after conclusion of the last cycle of the neoadjuvant study treatment. After definitive surgery, each participant will receive adjuvant study treatment (Pembrolizumab OR Placebo) for approximately 27 weeks (9 cycles). Following adjuvant study treatment, each participant will be monitored for safety, survival and disease recurrence. The primary study hypothesis is that pembrolizumab is superior to placebo, in combination with chemotherapy, as measured by the rate of Pathological Complete Response (pCR) and/or Event-free Survival (EFS), in participants with locally advanced TNBC.

Source references

references

citation
Schmid P, Cortes J, Dent R, McArthur H, Pusztai L, Kummel S, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Im SA, Untch M, Fasching PA, Mouret-Reynier MA, Foukakis T, Ferreira M, Cardoso F, Zhou X, Karantza V, Tryfonidis K, Aktan G, O'Shaughnessy J; KEYNOTE-522 Investigators. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med. 2024 Nov 28;391(21):1981-1991. doi: 10.1056/NEJMoa2409932. Epub 2024 Sep 15.
pmid
39282906
type
RESULT
citation
Kuemmel S, Fasching PA, Schmid P, Harbeck N, Takahashi M, Untch M, Boileau JF, Cortes J, Dent R, O'Shaughnessy J, Pusztai L, Foukakis T, Park YH, Hui R, Cardoso F, Denkert C, Jia L, Pan W, Karantza V, McArthur H. Surgical Outcomes After Neoadjuvant Pembrolizumab Plus Chemotherapy for Triple-Negative Breast Cancer: Results from the Randomized, Placebo-Controlled Phase 3 KEYNOTE-522 Study. Ann Surg Oncol. 2026 Jun;33(6):5550-5557. doi: 10.1245/s10434-026-19121-2. Epub 2026 Feb 25.
pmid
41739398
type
DERIVED
citation
Takahashi M, Mukai H, Takano T, Tsugawa K, Inoue K, Itoh M, Watanabe J, Tanabe Y, Yamamoto N, Miyoshi Y, Watanabe K, Mukohara T, Kong Y, Shimura M, Beca F, Schmid P, Iwata H. Pembrolizumab for Early-Stage Triple-Negative Breast Cancer: KEYNOTE-522 Japan Subgroup Analysis. Cancer Sci. 2026 Apr;117(4):1106-1116. doi: 10.1111/cas.70307. Epub 2026 Jan 14.
pmid
41536071
type
DERIVED
citation
Dent R, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Haiderali A, Jia L, Nguyen AM, Pan W, O'Shaughnessy J, Schmid P. Neoadjuvant pembrolizumab plus chemotherapy/adjuvant pembrolizumab for early-stage triple-negative breast cancer: quality-of-life results from the randomized KEYNOTE-522 study. J Natl Cancer Inst. 2024 Oct 1;116(10):1654-1663. doi: 10.1093/jnci/djae129.
pmid
38913881
type
DERIVED
citation
Favre-Bulle A, Huang M, Haiderali A, Bhadhuri A. Cost-Effectiveness of Neoadjuvant Pembrolizumab plus Chemotherapy Followed by Adjuvant Pembrolizumab in Patients with High-Risk, Early-Stage, Triple-Negative Breast Cancer in Switzerland. Pharmacoecon Open. 2024 Jan;8(1):91-101. doi: 10.1007/s41669-023-00445-8. Epub 2023 Nov 24.
pmid
37999854
type
DERIVED
citation
Takahashi M, Cortes J, Dent R, Pusztai L, McArthur H, Kummel S, Denkert C, Park YH, Im SA, Ahn JH, Mukai H, Huang CS, Chen SC, Kim MH, Jia L, Li XT, Tryfonidis K, Karantza V, Iwata H, Schmid P. Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023 Nov 1;6(11):e2342107. doi: 10.1001/jamanetworkopen.2023.42107.
pmid
37966841
type
DERIVED
citation
Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O'Shaughnessy J; KEYNOTE-522 Investigators. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med. 2022 Feb 10;386(6):556-567. doi: 10.1056/NEJMoa2112651.
pmid
35139274
type
DERIVED
citation
Perez-Garcia J, Soberino J, Racca F, Gion M, Stradella A, Cortes J. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020 Sep;20(9):981-989. doi: 10.1080/14712598.2020.1769063. Epub 2020 May 25.
pmid
32450725
type
DERIVED
citation
Schmid P, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549.
pmid
32101663
type
DERIVED