A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab (MK-3475) in Combination With Cisplatin and 5-Fluorouracil Versus Placebo in Combination With Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects With Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590)
Overview
- Phase
- Phase 3
- Intervention
- Pembrolizumab
- Conditions
- Esophageal Neoplasms
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 749
- Locations
- 189
- Primary Endpoint
- Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic esophageal carcinoma.
The overall primary efficacy hypotheses are as follows:
- In participants with esophageal squamous cell carcinoma (ESCC), participants whose tumors are programmed cell death-ligand 1 (PD-L1)-positive (defined as combined positive score [CPS] ≥10), ESCC participants whose tumors are PD-L1 positive (CPS ≥10), and in all participants, overall survival (OS) is superior with pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy.
- In participants with ESCC, participants whose tumors are PD-L1 positive (CPS ≥10), and in all participants, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator is superior with pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the esophagogastric junction (EGJ)
- •Has measurable disease per RECIST 1.1 as determined by the local site investigator/radiology assessment
- •Eastern Cooperative Group (ECOG) performance status of 0 to 1
- •Can provide either a newly obtained or archival tissue sample for PD-L1 by immunohistochemistry analysis
- •Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to randomization and be willing to use an adequate method of contraception (e.g. abstinence, intrauterine device, diaphragm with spermicide, etc.) for the course of the study through 120 days after the last dose of study treatment and up to 180 days after last dose of cisplatin
- •Male participants of childbearing potential must agree to use an adequate method of contraception (e.g. abstinence, vasectomy, male condom, etc.) starting with the first dose of study treatment through 120 days after the last dose of study treatment and up to 180 days after last dose of cisplatin, and refrain from donating sperm during this period
- •Has adequate organ function
Exclusion Criteria
- •Has locally advanced esophageal carcinoma that is resectable or potentially curable with radiation therapy (as determined by local investigator)
- •Has had previous therapy for advanced/metastatic adenocarcinoma or squamous cell cancer of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ
- •Has had 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
- •Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ breast cancer that has undergone potentially curative therapy, and in situ or intramucosal pharyngeal cancer
- •Has known active central nervous system metastases and/or carcinomatous meningitis.
- •Has an active autoimmune disease that has required systemic treatment in past 2 years
- •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 to the first dose of study treatment, or has a history of organ transplant, including allogeneic stem cell transplant
- •Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis, or has an active infection requiring systemic therapy
- •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 after the last dose of study medication and up to 180 days after last dose of cisplatin
- •Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in a pembrolizumab (MK-3475) clinical trial
Arms & Interventions
Pembrolizumab + SOC
Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Intervention: Pembrolizumab
Pembrolizumab + SOC
Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Intervention: Cisplatin
Pembrolizumab + SOC
Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Intervention: 5-FU
Placebo + SOC
Participants receive placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Intervention: Placebo
Placebo + SOC
Participants receive placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Intervention: Cisplatin
Placebo + SOC
Participants receive placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Intervention: 5-FU
Outcomes
Primary Outcomes
Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10)
Time Frame: Up to approximately 34 months
Overall survival 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 is reported here for all participants of the Intent-To-Treat (ITT) population (all randomized) who had ESCC and who were PD-L1 CPS ≥10.
OS in Participants With ESCC
Time Frame: Up to approximately 34 months
Overall survival 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 is reported here for all participants of the ITT population (all randomized) who had ESCC.
OS in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)
Time Frame: Up to approximately 34 months
Overall survival 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 is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
OS in All Participants
Time Frame: Up to approximately 34 months
Overall survival 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 is reported here for all participants of the ITT population (all randomized).
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) As Assessed By Investigator in Participants With ESCC
Time Frame: Up to approximately 34 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who had ESCC.
PFS Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)
Time Frame: Up to approximately 34 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
PFS Per RECIST 1.1 As Assessed By Investigator in All Participants
Time Frame: Up to approximately 34 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized).
Secondary Outcomes
- Objective Response Rate (ORR) Per RECIST 1.1 As Assessed By Investigator in All Participants(Up to approximately 34 months)
- ORR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Up to approximately 34 months)
- ORR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC(Up to approximately 34 months)
- ORR Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Up to approximately 34 months)
- Duration of Response (DOR) Per RECIST 1.1 As Assessed By Investigator in All Participants(Up to approximately 34 months)
- DOR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Up to approximately 34 months)
- DOR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC(Up to approximately 34 months)
- DOR Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Up to approximately 34 months)
- Number of Participants With an Adverse Event (AE)(Up to approximately 28 months)
- Number of Participants Discontinuing Study Treatment Due to an AE(Up to approximately 27 months)
- Change From Baseline To Week 18 in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Combined Score in All Participants(Baseline, Week 18)
- Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Baseline, Week 18)
- Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC(Baseline, Week 18)
- Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Baseline, Week 18)
- Change From Baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Subscale Scores in All Participants(Baseline, Week 18)
- Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Baseline, Week 18)
- Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC(Baseline, Week 18)
- Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)(Baseline, Week 18)