Phase 3
N=749
First-line Esophageal Carcinoma Study With Pembrolizumab Plus Chemo vs. Chemo (MK-3475-590/KEYNOTE-590)
Esophageal Neoplasms
Bottom Line
View on ClinicalTrials.gov: NCT03189719 ↗Enrolled (actual)
749
Serious AEs
55.5%
Results posted
Jul 2021
Primary outcome: Primary: 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) — 13.9; 8.8 Months — p=<0.0001
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- Pembrolizumab (Biological); Placebo (Drug); Cisplatin (Drug); 5-FU (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Merck Sharp & Dohme LLC
- Primary completion
- Jul 2020
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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) |
13.9; 8.8 | <0.0001 sig |
| PRIMARY OS in Participants With ESCC |
12.6; 9.8 | 0.0006 sig |
| PRIMARY OS in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
13.5; 9.4 | <0.0001 sig |
| PRIMARY OS in All Participants |
12.4; 9.8 | <0.0001 sig |
| PRIMARY 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 |
6.3; 5.8 | <0.0001 sig |
| PRIMARY PFS Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
7.5; 5.5 | <0.0001 sig |
| PRIMARY PFS Per RECIST 1.1 As Assessed By Investigator in All Participants |
6.3; 5.8 | <0.0001 sig |
| SECONDARY Objective Response Rate (ORR) Per RECIST 1.1 As Assessed By Investigator in All Participants |
45.0; 29.3 | <0.0001 sig |
| SECONDARY ORR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
51.0; 28.0 | <0.0001 sig |
| SECONDARY ORR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC |
43.8; 31.0 | 0.0009 sig |
| SECONDARY ORR Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
51.1; 26.9 | <0.0001 sig |
| SECONDARY Duration of Response (DOR) Per RECIST 1.1 As Assessed By Investigator in All Participants |
8.3; 6.0 | — |
| SECONDARY DOR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
10.4; 4.4 | — |
| SECONDARY DOR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC |
9.1; 6.1 | — |
| SECONDARY DOR Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
10.4; 5.6 | — |
| SECONDARY Number of Participants With an Adverse Event (AE) |
370; 368 | — |
| SECONDARY Number of Participants Discontinuing Study Treatment Due to an AE |
90; 74 | — |
| SECONDARY 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 |
-1.74; -1.64 | 0.9530 |
| SECONDARY 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) |
-2.36; -0.40 | 0.5053 |
| SECONDARY Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC |
-2.00; -1.94 | 0.9742 |
| SECONDARY 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) |
-1.73; 0.04 | 0.4810 |
| SECONDARY Change From Baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Subscale Scores in All Participants |
-3.18; 2.36; -4.78; -1.85; -0.22; 0.71 | 0.0436 sig |
| SECONDARY Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
-5.11; 3.57; -2.55; -0.42; -0.16; 4.94 | 0.0564 |
| SECONDARY Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC |
-1.18; 3.32; -4.03; -2.33; -0.40; 1.09 | 0.1632 |
| SECONDARY Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) |
-7.18; 1.02; -3.51; 0.07; -0.52; 4.25 | 0.0317 sig |
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:
1. 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.
2. 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.
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
- Has severe hypersensitivity (≥ Grade 3) to any study treatment (pembrolizumab, cisplatin, or 5-FU) and/or any of its excipients
- Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis) or human immunodeficiency virus (HIV) infection
- Has known history of or is positive for hepatitis B or hepatitis C
- Has received a live vaccine within 30 days prior to the first dose of study treatment
- Has had radiotherapy within 14 days of randomization. Participants who received radiotherapy >14 days prior to randomization must have compl
Data sourced from ClinicalTrials.gov (NCT03189719). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.