NCT04210115 · CITED IN SOURCE DOCUMENTS

Study of Pembrolizumab (MK-3475) Versus Placebo in Participants With Esophageal Carcinoma Who Are Receiving Chemotherapy and Radiation Therapy (MK-3475-975/KEYNOTE-975)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2026-07-22

The purpose of this study is to assess the efficacy and safety of treatment with definitive chemoradiotherapy (dCRT) + pembrolizumab (MK-3475) compared to treatment with dCRT + placebo with respect to Event-free Survival (EFS) and Overall Survival (OS) in: * participants whose tumors express Programmed Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 * participants whose tumors express PD-L1 CPS ≥1 * all participants The primary study hypotheses are that dCRT+ pembrolizumab is better than dCRT + placebo with respect to: * EFS in participants whose tumors express PD-L1 CPS ≥10 * EFS in participants whose tumors express PD-L1 CPS ≥1 * EFS in all participants * OS in participants whose tumors express PD-L1 CPS ≥10 * OS in participants whose tumors express PD-L1 CPS ≥1 * OS in all participants

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

eligibility Criteria: Inclusion Criteria: * Has histologically or cytologically confirmed diagnosis of CTX N+ M0 or cT2-T4a NX M0 ESCC, GEJC, EAC, or histologically or cytologically confirmed diagnosis of cTX N+ M1 cervical or upper thoracic esophageal carcinoma with supraclavicular lymph node metastases only * Is deemed suitable for dCRT * Is ineligible for curative surgery based on the documented opinion of a qualified medical/surgical/radiation oncologist. * Is not expected to require tumor resection during the course of the study * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days of the first dose of study treatment * Has adequate organ function * Male participants must use adequate contraception (a male condom plus partner use of an additional contraceptive method) unless confirmed to be azoospermic (vasectomized or secondary to medical cause) and refrain from donating sperm during the study treatment period and through 90 days after the last dose of chemotherapy * Female participants who are a Woman of Childbearing Potential (WOCBP) must use contraception that is highly effective (with a failure rate of \<1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the study treatment period through 180 days after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab, whichever is greater, and agree not to donate eggs to others or freeze/store for her own use for the purpose of reproduction during this period * Female participants must not be pregnant or breastfeeding Exclusion Criteria: * Has direct invasion of tumor into adjacent organs such as the aorta or trachea or has radiographic evidence of \>90 degree encasement or invasion of a major blood vessel, or of intratumoral cavitation * Has had major surgery other than for insertion of a feeding tube, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipates the need for major surgery during study treatment; participants with gastric or esophageal fistulae are excluded * Has had weight loss of \>20% in the previous 3 months * Has had prior chemotherapy or radiotherapy for esophageal cancer * Has had a myocardial infarction within the past 6 months * Has symptomatic congestive heart failure * Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137) * Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention; administration of killed vaccines is allowed * Has received any prior systemic anticancer therapy for esophageal cancer including investigational agents * Has not recovered from all adverse events (AEs) due to previous non-anticancer therapies to ≤Grade 1 or Baseline * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded from the study. Participants with localized prostate cancer that has undergone potentially curative treatment can be enrolled in the study. * Has severe hypersensitivity (≥Grade 3) to pembrolizumab, any of the study chemotherapy agents, or their excipients * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of Hepatitis B or known active Hepatitis C virus infection * Has a known history of active tuberculosis (TB; Bacillus tuberculosis) * 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 treatment (180 days for participants receiving cisplatin who are breastfeeding) * Has had an allogeneic tissue/solid organ transplant
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants receive pembrolizumab 200 mg on Day 1 of each 3-week cycle for 8 cycles followed by pembrolizumab 400 mg on Day 1 of each 6-week cycle for 5 cycles PLUS either: * FP therapy: cisplatin 75 mg/m\^2 on Day 1 of Weeks 1, 5, 8 and 11 PLUS 5-fluorouracil (5-FU)\] 1000 mg/m\^2 per day on Days 1-4 of Weeks 1, 5, 8 and 11 OR 800 mg/m\^2/day on each of Days 1-5 at Weeks 1, 5, 8, and 11 PLUS radiotherapy (either 50 Gray \[Gy\] in 25 fractions OR 60 Gy in 30 fractions) on Days 1-5 of each 3-week cycle OR * FOLFOX therapy: oxaliplatin 85 mg/m\^2 AND either leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 PLUS either 5-FU 400 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 OR 5-FU 800 mg/m\^2 per day on Days 1 and 2 of Weeks 1, 3, 5, 7, 9 and 11 PLUS radiotherapy (50 Gy in 25 fractions) on Days 1-5 of each 3-week cycle. All treatments except radiotherapy are given by intravenous (IV) infusion. Total treatment duration is approximately 1 year.
intervention Names
Biological: pembrolizumab
Drug: cisplatin
Drug: 5-FU
Radiation: radiotherapy
Drug: leucovorin
Drug: levoleucovorin
Drug: oxaliplatin
label
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
type
EXPERIMENTAL
description
Participants receive placebo on Day 1 of each 3-week cycle for 8 cycles followed by placebo on Day 1 of each 6-week cycle for 5 cycles PLUS either: * FP therapy: cisplatin 75 mg/m\^2 on Day 1 of Weeks 1, 5, 8 and 11 PLUS 5-FU 1000 mg/m\^2 per day on Days 1-4 of Weeks 1, 5, 8 and 11 OR 800 mg/m\^2/day on each of Days 1-5 at Weeks 1, 5, 8, and 11 PLUS radiotherapy (either 50 Gy in 25 fractions OR 60 Gy in 30 fractions) on Days 1-5 of each 3-week cycle OR * FOLFOX therapy: oxaliplatin 85 mg/m\^2 AND either leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 PLUS either 5-FU 400 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 OR 5-FU 800 mg/m\^2 per day on Days 1 and 2 of Weeks 1, 3, 5, 7, 9 and 11 PLUS radiotherapy (50 Gy in 25 fractions) on Days 1-5 of each 3-week cycle. All treatments except radiotherapy are given by IV infusion. Total treatment duration is approximately 1 year.
intervention Names
Drug: placebo
Drug: cisplatin
Drug: 5-FU
Radiation: radiotherapy
Drug: leucovorin
Drug: levoleucovorin
Drug: oxaliplatin
label
Placebo+FP or FOLFOX Therapy+Radiotherapy
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
pembrolizumab
other Names
MK-3475
KEYTRUDA®
type
BIOLOGICAL
arm Group Labels
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
placebo
other Names
Normal saline solution
type
DRUG
arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
cisplatin
other Names
PLATINOL®
type
DRUG
arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
5-FU
other Names
ADRUCIL®
type
DRUG
arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
external radiation
name
radiotherapy
type
RADIATION
arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
leucovorin
other Names
calcium folinate
folinic acid
type
DRUG
arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
levoleucovorin
other Names
FUSILEV®
calcium levofolinate
levofolinic acid
type
DRUG
arm Group Labels
Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
Placebo+FP or FOLFOX Therapy+Radiotherapy
description
IV infusion
name
oxaliplatin
other Names
ELOXATIN®
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: TRIPLE
who Masked: PARTICIPANT
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 703
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
EFS is defined as the time from randomization to an event defined as local, regional, or distant radiological recurrence as assessed by the investigator; clinical recurrence as assessed by the investigator with histopathologic confirmation (in the absence of radiological disease recurrence by investigator assessment); or death from any cause, whichever occurs first.
measure
Event-free Survival (EFS)
time Frame
Up to ~60 months
description
OS is defined as the time from randomization to death from any cause.
measure
Overall Survival (OS)
time Frame
Up to ~72 months

secondary Outcomes

description
An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment.
measure
Number of participants with an adverse event (AE)
time Frame
Up to ~15 months
description
An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment.
measure
Number of participants discontinuing study treatment due to an adverse event (AE)
time Frame
Up to ~12 months

Full study description

brief Summary: The purpose of this study is to assess the efficacy and safety of treatment with definitive chemoradiotherapy (dCRT) + pembrolizumab (MK-3475) compared to treatment with dCRT + placebo with respect to Event-free Survival (EFS) and Overall Survival (OS) in: * participants whose tumors express Programmed Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 * participants whose tumors express PD-L1 CPS ≥1 * all participants The primary study hypotheses are that dCRT+ pembrolizumab is better than dCRT + placebo with respect to: * EFS in participants whose tumors express PD-L1 CPS ≥10 * EFS in participants whose tumors express PD-L1 CPS ≥1 * EFS in all participants * OS in participants whose tumors express PD-L1 CPS ≥10 * OS in participants whose tumors express PD-L1 CPS ≥1 * OS in all participants
detailed Description: Participants receive pembrolizumab or placebo PLUS one of two chemotherapy regimens PLUS radiation therapy for up to approximately one year. The chemotherapy regimens are either: * FP (5-fluorouracil \[5-FU\] + cisplatin) or * FOLFOX (5-FU + oxaliplatin + leucovorin or levoleucovorin).

Source references

references

citation
Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, Mamon HJ, Moehler M, Fu X, Cho BC, Bordia S, Bhagia P, Shih CS, Desai A, Enzinger P. KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Future Oncol. 2021 Apr;17(10):1143-1153. doi: 10.2217/fon-2020-0969. Epub 2021 Feb 3.
pmid
33533655
type
DERIVED