A Randomized, Active-Controlled, Partially Blinded, Biomarker Select, Phase III Clinical Trial of Pembrolizumab as Monotherapy and in Combination With Cisplatin+5-Fluorouracil Versus Placebo+Cisplatin+5-Fluorouracil as First-Line Treatment in Subjects With Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 763
- 主要终点
- Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10
研究概览
简要总结
This is a study of pembrolizumab (MK-3475) as first-line treatment for participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Participants whose tumors express programmed death-ligand 1 (PD-L1) will be randomly assigned to one of the three treatment arms of the study: pembrolizumab as monotherapy [pembro mono], pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine [pembro combo], or placebo plus SOC chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine [SOC].
The primary study hypotheses are that pembrolizumab in combination with SOC chemotherapy is superior to SOC chemotherapy alone in terms of Progression-free Survival (PFS) and Overall Survival (OS) in participants with PD-L1 Combined Positive Score (CPS) ≥1, pembrolizumab in combination with SOC chemotherapy is superior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥10, pembrolizumab monotherapy is non-inferior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥1, and pembrolizumab monotherapy is superior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥1 and in participants with PD-L1 CPS ≥10.
详细描述
As specified by the protocol, primary and secondary efficacy analyses will be evaluated in gastric cancer participants with PD-L1 CPS ≥1 (all participants) and PD-L1 CPS ≥10 (OS) by comparing the pembro mono arm or pembro combo arm separately to the SOC arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This study is partially blinded. The participant, study site personnel, and the sponsor will be blinded in the pembrolizumab plus SOC chemotherapy (pembro combo) arm and the placebo plus SOC chemotherapy (SOC) arm, but not in the pembro monotherapy (mono arm) since only one type of study medication will be administered.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to first dose of study medication
- •Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma
- •Human epidermal growth factor receptor 2- (HER2/neu-) negative and programmed cell death ligand 1 (PD-L1)-positive
- •Has measurable disease
- •Female participants of childbearing potential must be willing to use adequate contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
- •Male participants of childbearing potential should agree to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study medication
- •Adequate organ function
排除标准
- •Squamous cell or undifferentiated gastric cancer
- •Previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participant may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization
- •Major surgery, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study treatment.
- •Radiotherapy within 14 days of randomization
- •Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- •Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Active autoimmune disease that has required systemic treatment in past 2 years
- •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 medication
- •History of non-infectious pneumonitis that required steroids or current pneumonitis
- •Active infection requiring systemic therapy
- •Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication
- •Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, or anti-PD-L2 agent
- •Known history of human immunodeficiency virus (HIV)
- •Known active Hepatitis B or C
- •Currently participating in and receiving study therapy or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study medication
- •Received a live vaccine within 30 days prior to the first dose of study medication
研究组 & 干预措施
Pembrolizumab Monotherapy (Pembro Mono)
Participants will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W). Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Pembrolizumab (Biological)
Pembrolizumab + SOC Chemotherapy (Pembro Combo)
Participants will receive pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W may be substituted for 5-FU per local guidelines. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Pembrolizumab (Biological)
Pembrolizumab + SOC Chemotherapy (Pembro Combo)
Participants will receive pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W may be substituted for 5-FU per local guidelines. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Cisplatin (Drug)
Pembrolizumab + SOC Chemotherapy (Pembro Combo)
Participants will receive pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W may be substituted for 5-FU per local guidelines. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: 5-FU (Drug)
Pembrolizumab + SOC Chemotherapy (Pembro Combo)
Participants will receive pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W may be substituted for 5-FU per local guidelines. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Capecitabine (Drug)
Placebo + SOC Chemotherapy (SOC)
Participants receive placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W may be substituted for 5-FU per local guidelines.
干预措施: Cisplatin (Drug)
Placebo + SOC Chemotherapy (SOC)
Participants receive placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W may be substituted for 5-FU per local guidelines.
干预措施: 5-FU (Drug)
Placebo + SOC Chemotherapy (SOC)
Participants receive placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W may be substituted for 5-FU per local guidelines.
干预措施: Capecitabine (Drug)
Placebo + SOC Chemotherapy (SOC)
Participants receive placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W may be substituted for 5-FU per local guidelines.
干预措施: Placebo (Drug)
结局指标
主要结局
Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro mono arm and SOC arm and is presented later in the record.
Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥10
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro combo arm and SOC arm and is presented earlier in the record.
Pembro Combo vs SOC: Overall Survival (OS) in Participants With PD-L1 CPS ≥1 (All Participants)
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.
Pembro Combo vs SOC: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 (All Participants)
时间窗: Up to approximately 36 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population. PFS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record.
Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥1 (All Participants)
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record.
次要结局
- Number of Participants Experiencing an Adverse Event (AE)(Up to approximately 33 months)
- Pembro Mono vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-Module for Gastric Cancer (STO22) Pain Symptom Subscale Score(Baseline, Week 18)
- Pembro Combo vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-STO22 Pain Symptom Subscale Score(Baseline, Week 18)
- Number of Participants Discontinuing Study Treatment Due to an AE(Up to approximately 30 months)
- Pembro Mono vs SOC: DOR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)(Up to approximately 42 months)
- Pembro Mono vs SOC: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score(Baseline, Week 18)
- Pembro Combo vs SOC: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)(Up to approximately 42 months)
- Pembro Combo vs SOC: Duration of Response (DOR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)(Up to approximately 42 months)
- Pembro Mono vs SOC: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)(Up to approximately 42 months)
- Pembro Mono vs SOC: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)(Up to approximately 42 months)
- Pembro Combo vs SOC: Change From Baseline to Week 18 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score(Baseline, Week 18)