Phase 3 Randomized Study of Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy in HR+/HER2- Metastatic Breast Cancer
- Trial ID
- 2023-506752-24-00
- Protocol
- MK-3475-B49
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **pembrolizumab** plus chemotherapy to placebo plus chemotherapy with respect to **progression-free survival (PFS)** per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR) in participants with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. This is clinically relevant as it aims to determine the efficacy of pembrolizumab in prolonging the time patients live without disease progression, which is a critical measure of treatment effectiveness in locally recurrent inoperable or metastatic HR+/HER2- breast cancer.
Secondary objectives include: - Comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to overall survival (OS) in participants with PD-L1 CPS ≥1 and CPS ≥10 tumors. - Comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to PFS per RECIST 1.1 as assessed by BICR in participants with CPS ≥10 tumors. - Comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to PFS per RECIST 1.1 as assessed by investigator in participants with PD-L1 CPS ≥10 and CPS ≥1 tumors, separately. - Comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to objective response rate (ORR) per RECIST 1.1 as assessed by BICR in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately. - Comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to disease control rate (DCR) per RECIST 1.1 as assessed by BICR in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately. - Evaluating duration of response (DOR) per RECIST 1.1 as assessed by BICR in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately. - Evaluating health-related quality of life (HRQoL) assessments using the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30) in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately. - Evaluating safety and tolerability of pembrolizumab plus chemotherapy.
Participants
The clinical trial involves a total of **216 participants** diagnosed with **locally recurrent inoperable or metastatic HR+/HER2- breast cancer**, who have not previously received cytotoxic chemotherapy in a noncurative setting. The study population includes both **female and male subjects**, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including progression on prior endocrine therapy and eligibility for chemotherapy. The trial population is characterized by a requirement for adequate organ function and an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1. Lifestyle considerations such as the use of contraception are relevant, particularly for women of childbearing potential and male participants, to prevent pregnancy during and after the trial period. The study also includes individuals with stable doses of bisphosphonates or RANK ligand inhibitors, and those with a history of Hepatitis B or C, provided certain conditions are met. The trial does not exclude vulnerable populations, indicating a broad inclusion strategy to assess the efficacy of pembrolizumab combined with chemotherapy compared to a placebo in improving progression-free survival.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, Phase 3 study** to evaluate the efficacy and safety of pembrolizumab in combination with chemotherapy compared to placebo plus chemotherapy in participants with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally recurrent inoperable or metastatic breast cancer. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with overall survival (OS) and other secondary endpoints evaluated in participants with a combined positive score (CPS) of ≥1. The trial is expected to run from August 2021 to September 2027, with participant involvement lasting up to 156 weeks, depending on the treatment arm and response to therapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as disease progression, prior treatment history, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. These visits will include assessments per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent central review. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent.
Inclusion criteria require participants to have measurable disease, a documented progression on prior endocrine therapy, and to be candidates for chemotherapy. Exclusion criteria are not specified in the provided data. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will ensure that all participants provide informed consent and adhere to contraceptive guidelines to prevent pregnancy during and after the study period.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Capecitabine** is administered in an oral pharmaceutical form with a maximum daily dose of 2000 mg/m². The total maximum dose is 3,080,000 mg/m² over a treatment period of up to 76 weeks. This medication is of chemical origin and is not a pediatric formulation.
**Doxorubicin** is provided in an intravenous form with a maximum daily dose of 50 mg/m² and a total maximum dose of 4128 mg/m² over 76 weeks. It is also of chemical origin and is not formulated for pediatric use. **Doxorubicin Hydrochloride, Liposomal** is similarly administered intravenously with the same dosing parameters as doxorubicin, and it is categorized under specified substance group 1.
**Paclitaxel** is administered intravenously with a maximum daily dose of 90 mg/m² and a total maximum dose of 22,291 mg/m² over 76 weeks. It is of chemical origin. **Paclitaxel Albumin-Bound** is also administered intravenously with a maximum daily dose of 100 mg/m² and a total maximum dose of 24,768 mg/m² over the same period, and it is categorized under specified substance group 1.
**Pembrolizumab**, marketed as Keytruda, is administered as a 25 mg/mL concentrate for solution for infusion. It is given intravenously with a maximum daily dose of 200 mg and a total maximum dose of 10,400 mg over 156 weeks. Pembrolizumab is a biological product and is not a pediatric formulation.
The study also includes non-experimental treatments in the form of placebos. The **Placebo to Keytruda - Normal Saline** and **Placebo to Keytruda - Dextrose** are used as comparator treatments. These placebos do not contain active substances and are not administered in a specific pharmaceutical form or route.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy and safety of these treatments in participants with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally recurrent inoperable or metastatic breast cancer.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by a Blinded Independent Central Review (BICR) in participants with a Combined Positive Score (CPS) of ≥1. Secondary endpoints include Overall Survival (OS) in participants with CPS ≥1 and CPS ≥10, PFS per RECIST 1.1 by BICR and by Investigator in participants with CPS ≥10 and CPS ≥1, Objective Response Rate (ORR), Disease Control Rate (DCR), and Duration of Response (DOR) per RECIST 1.1 by BICR in participants with CPS ≥10 and CPS ≥1.
Additional secondary endpoints involve changes from baseline in various scores on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), including Global Health Status/Quality of Life, Physical Functioning, Emotional Functioning, Fatigue, and Diarrhea, in participants with CPS ≥10 and CPS ≥1. Time to Deterioration (TTD) in these scores will also be measured. The percentage of participants experiencing an Adverse Event (AE) and those discontinuing the study drug due to an AE will be recorded.
Inclusion and Exclusion Criteria
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
- 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 Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Aug 2021 | 6 |
 France | Not Recruiting | 01 Aug 2021 | 80 |
 Germany | Not Recruiting | 01 Aug 2021 | 24 |
 Greece | Not Recruiting | 01 Aug 2021 | 13 |
 Hungary | Not Recruiting | 01 Aug 2021 | 15 |
 Ireland | Not Recruiting | 01 Aug 2021 | 3 |
 Italy | Not Recruiting | 01 Aug 2021 | 20 |
 The Netherlands | Not Recruiting | 01 Aug 2021 | — |
 Poland | Not Recruiting | 01 Aug 2021 | 24 |
 Portugal | Not Recruiting | 01 Aug 2021 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DOXORUBICIN | Other | PHF00231MIG | INTRAVENOUS | 50 | 76 | SCP1712543 |
DOXORUBICIN HYDROCHLORIDE, LIPOSOMAL | Other | — | INTRAVENOUS | 50 | 76 | SUB126795 |
PACLITAXEL ALBUMIN-BOUND | Other | — | INTRAVENOUS | 100 | 76 | SUB127678 |
Placebo to Keytruda - Normal Saline | Placebo | N/A | — | — | — | N/A |
PACLITAXEL | Other | PHF00016MIG | INTRAVENOUS | 90 | 76 | SCP247399 |
Placebo to Keytruda - Dextrose | Placebo | N/A | — | — | — | N/A |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 156 | PRD4323105 |
CAPECITABINE | Other | PHF00009MIG | ORAL | 2000 | 76 | SCP2172075 |