Clinical trial NCT02819518: 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)
Official title: A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer - (KEYNOTE-355)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-06-30
Enrollment: 882
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

1. the combination of pembrolizumab and chemotherapy prolongs Progression-Free Survival (PFS) compared to placebo and chemotherapy in:

   * 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
2. 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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.
* Has a known history of human immunodeficiency virus (HIV).
* Has known active hepatitis B or hepatitis C.
* Has received a live vaccine within 30 days prior to randomization.
* Has a known history of hypersensitivity or allergy to pembrolizumab and any of its components and/or to any of the study chemotherapies (e.g., nab-paclitaxel, paclitaxel, gemcitabine, or carboplatin) and any of their components.
* Is receiving any medication prohibited in combination with study chemotherapies as described in the respective product labels, unless medication was stopped within 7 days prior to randomization.

Primary outcomes:
measure: Part 1: Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants
timeFrame: Up to approximately 39 months
measure: Part 1: Percentage of Participants Who Discontinued Study Drug Due to an AE - All Participants
timeFrame: Up to approximately 39 months
measure: Part 2: Progression-Free Survival (PFS) - All Participants
timeFrame: Up to approximately 53 months
measure: Part 2: PFS - Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: PFS - Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: Overall Survival (OS) - All Participants
timeFrame: Up to approximately 53 months
measure: Part 2: OS - Participants With PD-L1 CPS ≥1 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: OS - Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Up to approximately 53 months
Secondary outcomes:
measure: Part 2: Objective Response Rate (ORR) - All Participants
timeFrame: Up to approximately 53 months
measure: Part 2: ORR - Participants With PD-L1 CPS ≥1 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: ORR - Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: Duration of Response (DOR) - All Participants
timeFrame: Up to approximately 53 months
measure: Part 2: DOR - Participants With PD-L1 CPS ≥1 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: DOR - Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: Disease Control Rate (DCR) - All Participants
timeFrame: Up to approximately 53 months
measure: Part 2: DCR - Participants With PD-L1 CPS ≥1 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: DCR - Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Up to approximately 53 months
measure: Part 2: Percentage of Participants Who Experienced an AE- All Participants
timeFrame: Up to approximately 81 months
measure: Part 2: Percentage of Participants Who Discontinued Study Drug Due to an AE- All Participants
timeFrame: Up to approximately 81 months
measure: Part 2: Change From Baseline to Week 15 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score- All Participants
timeFrame: Baseline and Week 15
measure: Part 2: Change From Baseline to Week 15 in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score - Participants With PD-L1 CPS ≥1 Tumors
timeFrame: Baseline and Week 15
measure: Part 2: Change From Baseline to Week 15 in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score-Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Baseline and Week 15
measure: Part 2: Change From Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23)-All Participants
timeFrame: Baseline and Week 15
measure: Part 2: Change From Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 - Participants With PD-L1 CPS ≥1 Tumors
timeFrame: Baseline and Week 15
measure: Part 2: Change From Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC QLQ-BR23- Participants With PD-L1 CPS ≥10 Tumors
timeFrame: Baseline and Week 15
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.