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Immune Checkpoint Inhibitors

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.

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.

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.

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.

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.

Nab-paclitaxel

Normale Saline Solution

Medical Director

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.

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)

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)

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

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.

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.

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.

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.

Objective response rate is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experienced a CR or PR as assessed by BICR based on RECIST 1.1 is presented.

For participants who demonstrate a confirmed CR (Disappearance of all target lesions) or confirmed PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first, based on assessments by BICR per RECIST 1.1. Per RECIST 1.1, PD was defined as at least a 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 at least 5 mm. The appearance of one or more new lesions was also considered PD.

Disease control rate is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) or have demonstrated stable disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD\]) for at least 24 weeks, based on assessments by BICR per RECIST 1.1.

The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score are presented.

EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects were scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score denotes worse symptoms for the systemic therapy side effects symptom scale. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score is presented.

EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score denotes worse symptoms for the systemic therapy side effects symptom scale. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score is presented.

Merck Sharp & Dohme LLC

The population for all cause mortality includes all participants in the treatment arm to which they were randomly assigned. The population for AEs includes all participants who received at least 1 dose of study intervention in the arm of the study intervention received. 4 participants assigned to the Part 1: pembrolizumab + paclitaxel group received incorrect chemotherapy in error: 3 participants received pembrolizumab + nab-paclitaxel and 1 received pembrolizumab + gemcitabine/carboplatin.

Participants received 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.

Part 1: Pembrolizumab + Nab-paclitaxel

Participants received 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.

Part 1: Pembrolizumab + Paclitaxel

Participants received 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.

Part 1: Pembrolizumab + Gemcitabine/Carboplatin

Participants received 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.

Part 2: Pembrolizumab + Chemotherapy (First Course)

Eligible participants received up to 17 additional administrations (up to approximately 1 year) of pembrolizumab 200 mg IV on day 1 of each 21-day cycle.

Part 2: Pembrolizumab + Chemotherapy (Second Course)

Participants received 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.

Part 2: Placebo + Chemotherapy

Participants received 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. Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to \~1 year).

Part 2: Pembrolizumab + Chemotherapy

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

PD-L1 protein expression in triple-negative breast cancer (TNBC) is determined by using CPS, which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The number of participants with PD-L1 Status CPS\<1 and CPS≥1 at baseline is presented.

Programmed Cell Death Ligand 1 (PD-L1) Status (Combined Positive Score [CPS] Cutoff of 1)

PD-L1 protein expression in TNBC is determined by using CPS, which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The number of participants with PD-L1 Status CPS\<10 and CPS≥10 at baseline is presented.

PD-L1 Status (CPS Cutoff of 10)

Senior Vice President, Global Clinical Development

All randomly assigned participants who received at least 1 dose of study intervention were included in the group corresponding to the study intervention actually received. Four participants assigned to the pembrolizumab + paclitaxel group received incorrect chemotherapy in error: 3 participants received pembrolizumab + nab-paclitaxel and 1 received pembrolizumab + gemcitabine/carboplatin.

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

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

Participants were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment

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

Participants with PD-L1 CPS ≥1 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment

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

Participants with PD-L1 CPS ≥10 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment

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

Part 2: Overall Survival (OS) - All Participants

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

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

Participants received placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one 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.

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

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

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

All randomized participants, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.

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

All randomized participants with PD-LI CPS ≥1 tumors regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.

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

All randomized participants with PD-LI CPS ≥10 tumors regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.

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

Part 2: Disease Control Rate (DCR) - All Participants

Participants with PD-L1 CPS ≥1 tumors at baseline were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment

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

Participants with PD-L1 CPS ≥10 tumors at baseline were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment

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

All randomized participants who received at least 1 dose of study intervention. Participants were included in the group corresponding to the study intervention actually received.

Part 2: Percentage of Participants Who Experienced an AE- All Participants

Part 2: Percentage of Participants Who Discontinued Study Drug Due to an AE- All Participants

All randomized participants who received at least 1 dose of study intervention and had completed at least 1 patient-reported outcome (PRO) assessment. Participants were included in the treatment arm to which they were randomly assigned.

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

All randomized participants with PD-L1 CPS ≥1 tumors who received at least 1 dose of study intervention and had completed at least 1 patient-reported outcome (PRO) assessment. Participants were included in the treatment arm to which they were randomly assigned.

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

All randomized participants with PD-L1 CPS ≥10 tumors who received at least 1 dose of study intervention and had completed at least 1 patient-reported outcome (PRO) assessment. Participants were included in the treatment arm to which they were randomly assigned.

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

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

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

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

Participants received 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

Spots Global Cancer Trial Database for normale saline solution