Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy for HR+/HER2- Locally Recurrent Inoperable or Metastatic Breast Cancer (MK-3475-B49/KEYNOTE-B49)

Merck Sharp & Dohme (MSD)

Status and phase

Active, not recruiting

Phase 3

Conditions

Breast Neoplasms

Treatments

Drug: dextrose

Drug: liposomal doxorubicin

Biological: pembrolizumab

Drug: nab-paclitaxel

Drug: capecitabine

Drug: paclitaxel

Drug: normal saline

Study type

Interventional

Funder types

Industry

Identifiers

NCT04895358

U1111-1294-3354 (Other Identifier)

3475-B49

2020-005407-38 (EudraCT Number)

jRCT2051210049 (Registry Identifier)

2023-506752-24 (Other Identifier)

MK-3475-B49 (Other Identifier)

KEYNOTE-B49 (Other Identifier)

PHRR210721-003751 (Registry Identifier)

Details and patient eligibility

About

The safety and efficacy of pembrolizumab plus the investigator's choice of chemotherapy will be assessed compared to placebo plus the investigator's choice of chemotherapy in the treatment of chemotherapy-candidate hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally recurrent inoperable or metastatic breast cancer.

The primary hypotheses are that the combination of pembrolizumab and chemotherapy is superior to placebo and chemotherapy in regards to Progression-Free Survival (PFS) in participants with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥1.

Enrollment

340 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

The key inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

Has locally recurrent inoperable or metastatic HR+/HER2- breast cancer, which has not been previously treated with cytotoxic chemotherapy in the noncurative setting
Has progressed on prior endocrine therapy and is now a chemotherapy candidate, meeting the characteristics in regard to previous treatments of one of the following 4 groups:
Group 1: Has progressed on 2 or more lines of endocrine therapy for advanced/metastatic HR+/HER2-disease, with at least given in combination with a Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Prior treatment with mTOR and/or PI3-K inhibitors is allowed. OR
GROUP 2a: Has progressed on 1 line of previous endocrine therapy for advanced/metastatic disease AND had a disease recurrence within 24 months of definitive surgery for the primary tumor and while on adjuvant endocrine therapy. Prior use of CDK4/6 inhibitors is required, either in the adjuvant and/or metastatic setting. Prior treatment with mTOR and/or PI3-K inhibitors is allowed. OR
GROUP 2b: Has progressed within 12 months of starting 1 line of endocrine therapy with a CDK4/6 inhibitor for advanced/metastatic HR+/HER2- disease. OR
GROUP 3: If no prior treatment with a CDK4/6 inhibitor, for advanced/metastatic disease and/or early stage disease (adjuvant), participants must have progressed within 6 months of starting 1 line of endocrine therapy with or without an mTOR or PI3-K inhibitor for metastatic disease AND had a relapse within 24 months of definitive surgery for primary tumor and while receiving adjuvant endocrine therapy.
Has presented a documented radiographic disease progression (as assessed by the investigator and/or histology [biopsy or cytology] for participants presenting with new metastatic lesions) during or after the last administered endocrine therapy prior to entering the study.
Is a chemotherapy candidate that meets the criteria specified in the protocol
Provides a new or the last obtained core biopsy, preferably consisting of multiple cores, taken from a locally recurrent or a distant (metastatic) lesion not previously irradiated
Has centrally confirmed PD-L1 CPS ≥1 and HR+ (estrogen receptor [ER] and/or progesterone receptor [PgR]) /HER2- breast cancer as defined by the most recent American Society of Clinical Oncology (ASCO)/(College of American Pathologists) CAP guidelines on most recent tumor biopsy
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to the first dose of study treatment
Has adequate organ function within 10 days prior to the start of study
Male participants must agree to the following during the treatment period and for at least 6 months after the last dose of chemotherapy: refrain from donating sperm PLUS either be abstinent from heterosexual intercourse as their preferred and usual lifestyle or use contraception and agree to use a male condom plus partner use of an additional contraceptive
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a highly-effective contraceptive method during the treatment period and for at least 120 days after the last dose of pembrolizumab and 180 days after the last dose of chemotherapy (whichever occurs last), AND agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention
Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiologist
If receiving bisphosphonates or RANK ligand inhibitors, with stable doses for ≥4 weeks prior to the date of randomization, the participant may continue receiving this therapy during the study treatment. If participant needs to initiate these agents during the screening period, a bone scan to evaluate bone disease should be performed prior to randomization.
Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks prior to the first dose of study intervention and have undetectable HBV viral load prior to randomization
Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening

Exclusion Criteria:

Has breast cancer amenable to treatment with curative intent
Has a history or current evidence of any condition (e.g., transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the study, interfere with the participant's involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator
Has significant cardiac disease, such as: history of myocardial infarction, acute coronary syndrome, coronary angioplasty/stenting/bypass within the last 6 months, congestive heart failure (CHF) New York Heart association (NYHA) Class II-IV, or history of CHF NYHA Class III or IV
Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolving into life-threatening complications, such as lymphangitic lung metastases, bone marrow replacement, carcinomatous meningitis, significant symptomatic liver metastases, shortness of breath requiring supplemental oxygen, symptomatic pleural effusion requiring supplemental oxygen, symptomatic pericardial effusion, symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control
Has skin only disease
Has a known germline BRCA mutation (deleterious or suspected deleterious) and has not received previous treatment with PARP inhibition. either in the adjuvant or metastatic setting (where available and not medically contraindicated). Single-agent PARP inhibitor therapy does not count as a line of endocrine therapy.
Has received prior chemotherapy for locally recurrent inoperable or metastatic breast cancer
Has received prior therapy with an anti- programmed cell death 1 (PD-1), anti- programmed cell death ligand 1 (PD-L1), or anti- programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
Has received prior systemic anticancer therapy with other investigational agents within 4 weeks prior to randomization
Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids.
Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ excluding cancer in situ of bladder that have undergone potentially curative therapy
Has known active central nervous system (CNS) metastases
Has diagnosed carcinomatous meningitis
Has severe hypersensitivity to pembrolizumab and/or any of its excipients or has any hypersensitivity to the planned chemotherapy agent (paclitaxel, nab-paclitaxel, liposomal doxorubicin, or capecitabine) and/or any of their excipients
Has an active autoimmune disease that has required systemic treatment in past 2 years
Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
Has an active infection requiring systemic therapy
Has a known history of Human Immunodeficiency Virus (HIV) infection
Has a known COVID-19 infection (symptomatic or asymptomatic)
Has a known history of active tuberculosis (TB)
Has a known psychiatric or substance abuse disorder including alcohol or drug dependency that would interfere with the participant's ability to cooperate with the requirements of the study
Is breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days (or longer as specified by local institutional guidelines) after the last dose of study treatment
Has had an allogenic tissue/solid organ transplant

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Double Blind

340 participants in 2 patient groups

Pembrolizumab + Chemotherapy

Experimental group

Description:

Participants receive pembrolizumab 200 mg administered by intravenous infusion (IV) on Day 1 of each 21-day cycle (Q3W) PLUS one of four chemotherapy regimens: 1) paclitaxel 90 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day cycle (Q4W), 2) nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8, and 15 Q4W, 3) liposomal doxorubicin 50 mg/m\^2 IV on Day 1 Q4W, OR 4) capecitabine 1000 mg/m\^2 by oral administration (PO) twice a day (BID) on Days 1-14 Q3W for up to 35 administrations.

Treatment:

Drug: paclitaxel

Drug: capecitabine

Drug: nab-paclitaxel

Biological: pembrolizumab

Drug: liposomal doxorubicin

Placebo + Chemotherapy

Active Comparator group

Description:

Participants receive placebo (normal saline or dextrose) IV on Day 1 Q3W PLUS one of four chemotherapy regimens: 1) paclitaxel 90 mg/m\^2 IV on Days 1, 8, and 15 Q4W, 2) nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8, and 15 Q4W, 3) liposomal doxorubicin 50 mg/m\^2 IV on Day 1 Q4W, OR 4) capecitabine 1000 mg/m\^2 PO BID on Days 1-14 Q3W for up to 35 administrations.

Treatment:

Drug: normal saline

Drug: paclitaxel

Drug: capecitabine

Drug: nab-paclitaxel

Drug: liposomal doxorubicin

Drug: dextrose