Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs. Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (MK-3475-355/KEYNOTE-355)

NCT02819518 | Completed Phase 3 Results DMC

• 5 other identifiers: 3475-355163422MK-3475-355KEYNOTE-3552016-001432-35
• Study Type: interventional
• Target: 882
• Locations: 0 countries
• Sites: N/A

Brief Summary

The study will consist of two parts. In Part 1, the safety of pembrolizumab (MK-3475) in combination with one of three different chemotherapies will be assessed in the treatment of locally recurrent inoperable or metastatic triple negative breast cancer (TNBC), which has not been previously treated with chemotherapy. In Part 2, the safety and efficacy of pembrolizumab plus background chemotherapy will be assessed compared to the safety and efficacy of placebo plus background chemotherapy in the treatment of locally recurrent inoperable or metastatic TNBC, which has not been previously treated with chemotherapy. The primary hypotheses are that:

• all participants,
• participants with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors, and
• participants with PD-L1 CPS ≥10 tumors, and
• the combination of pembrolizumab and chemotherapy prolongs Overall Survival (OS) compared to placebo and chemotherapy in:
• all participants,
• participants with PD-L1 CPS ≥1 tumors, and
• participants with PD-L1 CPS ≥10 tumors.

Conditions

Triple Negative Breast Cancer (TNBC)

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1(PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Outcome Measures

Primary Outcomes (8)

• Part 1: Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants

  An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.

  Up to approximately 39 months

• Part 1: Percentage of Participants Who Discontinued Study Drug Due to an AE - All Participants

  An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.

  Up to approximately 39 months

• Part 2: Progression-Free Survival (PFS) - All Participants

  Progression-free survival was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) based on assessments by blinded independent central review (BICR) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD.

  Up to approximately 53 months

• Part 2: PFS - Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Tumors

  Progression-free survival was defined as the time from randomization to the first documented PD per RECIST 1.1 based on assessments by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD.

  Up to approximately 53 months

• Part 2: PFS - Participants With PD-L1 CPS ≥10 Tumors

  Progression-free survival was defined as the time from randomization to the first documented PD per RECIST 1.1 based on assessments by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD.

  Up to approximately 53 months

• Part 2: Overall Survival (OS) - All Participants

  Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.

  Up to approximately 53 months

• Part 2: OS - Participants With PD-L1 CPS ≥1 Tumors

  Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.

  Up to approximately 53 months

• Part 2: OS - Participants With PD-L1 CPS ≥10 Tumors

  Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.

  Up to approximately 53 months

Secondary Outcomes (17)

• Part 2: Objective Response Rate (ORR) - All Participants

  Up to approximately 53 months

• Part 2: ORR - Participants With PD-L1 CPS ≥1 Tumors

  Up to approximately 53 months

• Part 2: ORR - Participants With PD-L1 CPS ≥10 Tumors

  Up to approximately 53 months

• Part 2: Duration of Response (DOR) - All Participants

  Up to approximately 53 months

• Part 2: DOR - Participants With PD-L1 CPS ≥1 Tumors

  Up to approximately 53 months

Study Arms (5)

Part 1: Pembrolizumab + Nab-paclitaxel

EXPERIMENTAL

Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle.

Biological: Pembrolizumab; Drug: Nab-paclitaxel

Part 1: Pembrolizumab + Paclitaxel

EXPERIMENTAL

Participants receive pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS paclitaxel 90 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle.

Biological: Pembrolizumab; Drug: Paclitaxel

Part 1: Pembrolizumab + Gemcitabine/Carboplatin

EXPERIMENTAL

Participants receive pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS gemcitabine/carboplatin 1000 mg/m\^2 (gemcitabine) and an Area Under the Curve (AUC) 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

Biological: Pembrolizumab; Drug: Gemcitabine; Drug: Carboplatin

Part 2: Pembrolizumab + Chemotherapy

EXPERIMENTAL

Participants receive pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m\^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

Biological: Pembrolizumab; Drug: Nab-paclitaxel; Drug: Paclitaxel; Drug: Gemcitabine; Drug: Carboplatin

Part 2: Placebo + Chemotherapy

ACTIVE COMPARATOR

Participants receive placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m\^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

Drug: Nab-paclitaxel; Drug: Paclitaxel; Drug: Gemcitabine; Drug: Carboplatin; Drug: Normale Saline Solution

Interventions

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, KEYTRUDA®

Part 1: Pembrolizumab + Gemcitabine/Carboplatin; Part 1: Pembrolizumab + Nab-paclitaxel; Part 1: Pembrolizumab + Paclitaxel; Part 2: Pembrolizumab + Chemotherapy

Nab-paclitaxel DRUG

IV infusion

Also known as: ABRAXANE®

Part 1: Pembrolizumab + Nab-paclitaxel; Part 2: Pembrolizumab + Chemotherapy; Part 2: Placebo + Chemotherapy

Paclitaxel DRUG

IV infusion

Also known as: TAXOL®

Part 1: Pembrolizumab + Paclitaxel; Part 2: Pembrolizumab + Chemotherapy; Part 2: Placebo + Chemotherapy

Gemcitabine DRUG

IV infusion

Also known as: GEMZAR®

Part 1: Pembrolizumab + Gemcitabine/Carboplatin; Part 2: Pembrolizumab + Chemotherapy; Part 2: Placebo + Chemotherapy

Carboplatin DRUG

IV infusion

Also known as: PARAPLATIN®

Part 1: Pembrolizumab + Gemcitabine/Carboplatin; Part 2: Pembrolizumab + Chemotherapy; Part 2: Placebo + Chemotherapy

Normale Saline Solution DRUG

IV infusion

Part 2: Placebo + Chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has locally recurrent inoperable breast cancer not previously treated with chemotherapy and which cannot be treated with curative intent OR has metastatic breast cancer not previously treated with chemotherapy.
• Has centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology/college of American Pathologists (ASCO/CAP) guidelines.
• Has completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence.
• Has been treated with (neo)adjuvant anthracycline, if they received systemic treatment in the (neo)adjuvant setting, unless anthracycline was contraindicated or not considered the best treatment option for the participant in the opinion of the treating physician.
• Has measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by local radiology review.
• Has provided recently or newly obtained core or excisional biopsy from a locally recurrent inoperable or metastatic tumor lesion for central determination of TNBC status and PD-L1 expression, unless contraindicated due to site inaccessibility and/or participant safety concerns.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to the start of study drug.
• Has a life expectancy ≥12 weeks from randomization.
• Demonstrates adequate organ function, within 10 days prior to the start of study drug.
• Female participants are eligible to participate if they are not pregnant or breastfeeding AND they are not a woman of childbearing potential (WOCBP) OR is a WOCBP using a contraceptive method that is highly effective or is abstinent from heterosexual intercourse during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention AND has a negative highly-sensitive pregnancy test (\[urine or serum\] as required by local regulations) within 24 hours (urine) or 72 hours (serum) before the first dose of study intervention.
• Male participants are eligible to participate if they agree to refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention PLUS be abstinent from heterosexual intercourse OR must agree to use contraception unless confirmed to be azoospermic.

You may not qualify if:

• Is currently participating in a clinical study and receiving an investigational agent and/or using an investigational device, or has participated in a clinical study and received an investigational agent and/or used an investigational device within 4 weeks prior to randomization.
• Has not recovered (e.g., to ≤ Grade 1 or to baseline) from AEs due to a previously administered therapy.
• Has neuropathy ≥ Grade 2.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (e.g., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
• Has a known additional malignancy that progressed or required active treatment within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable brain metastases and did not receive chemotherapy for metastatic breast cancer.
• Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has active, or a history of, interstitial lung disease.
• Has a known history of active tuberculosis (TB).
• Has an active infection requiring systemic therapy.
• Has a history of Class II-IV congestive heart failure or myocardial infarction within 6 months of randomization.
• Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days (or longer as specified by local institutional guidelines) after the last dose of study drug.
• Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T cell receptor (such as cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137) or has previously participated in Merck pembrolizumab (MK-3475) clinical studies.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (3)

• Im SA, Cortes J, Cescon DW, Yusof MM, Iwata H, Masuda N, Takano T, Huang CS, Chung CF, Tsugawa K, Park YH, Matsumoto K, Inoue K, Kwong A, Loi S, Fu W, Pan W, Karantza V, Rugo HS, Schmid P. Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC. NPJ Breast Cancer. 2024 Sep 12;10(1):79. doi: 10.1038/s41523-024-00679-7.

  PMID: 39266535 DERIVED

• Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N, Torregroza Otero M, Gokmen E, Loi S, Guo Z, Zhou X, Karantza V, Pan W, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809.

  PMID: 35857659 DERIVED

• Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. doi: 10.1016/S0140-6736(20)32531-9.

  PMID: 33278935 DERIVED

Related Links

• Merck Clinical Trial Information
• Plain Language Summary

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; Paclitaxel; Gemcitabine; Carboplatin

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC.

ClinicalTrialsDisclosure@msd.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2016
• First Posted: June 30, 2016
• Study Start: July 27, 2016
• Primary Completion: June 15, 2021
• Study Completion: October 30, 2023
• Last Updated: November 27, 2024
• Results First Posted: July 5, 2022

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share