NCT02563002 · CITED IN SOURCE DOCUMENTS

Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)

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: 2024-10-03

In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

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

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor

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outcome · POSTED

Number of Participants Who Experienced an Adverse Event (AE)

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outcome · POSTED

Number of Participants Who Discontinued Study Treatment Due to an AE

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Locally confirmed dMMR or MSI-H stage IV colorectal carcinoma * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to study start * Life expectancy of at least 3 months * Measurable disease * Female participants of childbearing potential must be willing to use adequate contraception for the course of the study starting with the first dose of study medication through 180 days after the last dose of standard of care (SOC) therapy or 120 days after the last pembrolizumab dose * Male participants must agree to use adequate contraception for the course of the study starting with the first dose of study medication through 180 days after the last dose of study medication for chemotherapy arm (no contraception requirement for pembrolizumab \[MK-3475\] arm) * Adequate organ function Exclusion Criteria: * Has received prior systemic therapy for Stage IV colorectal cancer. May have received prior adjuvant chemotherapy for colorectal cancer as long as it was completed at least 6 months prior to randomization on this study * Currently participating and receiving treatment in another study, or participated in a study of an investigational agent and received treatment, or used an investigational device within 4 weeks of randomization * Active autoimmune disease that has required systemic treatment in past 2 years * Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization on this study * Radiation therapy within 4 weeks prior to randomization on this study and not recovered to baseline from adverse events due to radiation therapy * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization on this study * Has received prior therapy with an immune checkpoint inhibitor (e.g., anti-programmed cell death \[PD\]-1, anti-PD ligand 1 \[L1\], anti-PD-L2 agent, or anti-cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\] agent, etc.) * Another malignancy that is progressing or requires active treatment with the exception of non-melanomatous skin cancer that has undergone potentially curative therapy and in situ cervical carcinoma * Received a live or a live attenuated vaccine within 30 days of planned start of study medication * Known history of Human Immunodeficiency Virus (HIV), Hepatitis B or C * Known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis * Known history of active tuberculosis (Bacillus tuberculosis \[TB\]) * Active infection requiring systemic therapy * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study * Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of SOC (for male and female participants) or 120 days after the last dose of pembrolizumab (for female participants only)
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 intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 treatments (approximately 2 years). Participants that have stopped the initial course of pembrolizumab and have stable disease but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 year additional).
intervention Names
Biological: Pembrolizumab
label
Pembrolizumab
type
EXPERIMENTAL
description
Participants receive 1 of 6 possible standard chemotherapy regimens: mFOLFOX6, or mFOLFOX6+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or mFOLFOX6+cetuximab 400 mg/m\^2 IV over 2 hours then 250 mg/m\^2 over 1 hour weekly in each 2-week cycle, or FOLFIRI, or FOLFIRI+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or FOLFIRI+cetuximab 400 mg/m\^2 IV over 2 hours then 250 mg/m\^2 over 1 hour weekly in each 2-week cycle. Participants with documented disease progression following chemotherapy can crossover to receive pembrolizumab for up to 35 cycles (approximately 2 years). Participants that have stopped pembrolizumab and have stable disease but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 year additional).
intervention Names
Drug: mFOLFOX6
Drug: FOLFIRI
Biological: Pembrolizumab
Biological: Bevacizumab
Biological: Cetuximab
label
Standard of Care (SOC)
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Standard of Care (SOC)
description
Regimen consists of oxaliplatin 85 mg/m\^2 IV on Day 1, leucovorin 400 mg/m\^2 or levoleucovorin 200 mg/m\^2 IV on Day 1, 5-fluorouracil (5-FU) 400 mg/m\^2 IV bolus on Day 1 and then 1200 mg/m\^2/day IV over 2 days for total dose of 2400 mg/m\^2 in each 2-week cycle
name
mFOLFOX6
type
DRUG
arm Group Labels
Standard of Care (SOC)
description
Regimen consists of irinotecan 180 mg/m\^2 IV on Day 1, leucovorin 400 mg/m\^2 or levoleucovorin 200 mg/m\^2 IV on Day 1, 5-FU 400 mg/m\^2 IV bolus on Day 1 and then 1200 mg/m\^2/day IV over 2 days for total dose of 2400 mg/m\^2 in each 2-week cycle
name
FOLFIRI
type
DRUG
arm Group Labels
Pembrolizumab
Standard of Care (SOC)
description
IV infusion
name
Pembrolizumab
other Names
MK-3475
SCH 900475
KEYTRUDA®
type
BIOLOGICAL
arm Group Labels
Standard of Care (SOC)
description
IV infusion
name
Bevacizumab
type
BIOLOGICAL
arm Group Labels
Standard of Care (SOC)
description
IV infusion
name
Cetuximab
type
BIOLOGICAL

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 307
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on blinded central imaging vendor review 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Hazards ratio (HR) and associated 95% confidence intervals (CIs) from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol.
measure
Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor
time Frame
Up to approximately 59 months
description
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact. HR and associated 95% CIs from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol.
measure
Overall Survival (OS)
time Frame
Up to approximately 59 months

secondary Outcomes

description
ORR was defined as the percentage of the participants who experienced a Complete Response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 as assessed by the central imaging vendor. The percentage of participants who experienced a CR or PR was presented for the first course of study treatment per protocol.
measure
Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor
time Frame
Up to approximately 59 months
description
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE was presented for the first course study treatment per protocol.
measure
Number of Participants Who Experienced an Adverse Event (AE)
time Frame
Up to approximately 59 months
description
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented for the first course study treatment per protocol.
measure
Number of Participants Who Discontinued Study Treatment Due to an AE
time Frame
Up to approximately 59 months

Full study description

brief Summary: In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.

Source references

references

citation
Yoshino T, Andre T, Kim TW, Yong WP, Shiu KK, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Alcaide-Garcia J, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Le DT, Adachi N, Fogelman D, Marinello P, Diaz LA Jr. Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer. Cancer Sci. 2023 Mar;114(3):1026-1036. doi: 10.1111/cas.15650. Epub 2022 Dec 12.
pmid
36369901
type
DERIVED
citation
Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May;23(5):659-670. doi: 10.1016/S1470-2045(22)00197-8. Epub 2022 Apr 12.
pmid
35427471
type
DERIVED
citation
Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 May;22(5):665-677. doi: 10.1016/S1470-2045(21)00064-4. Epub 2021 Apr 1.
pmid
33812497
type
DERIVED
citation
Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699.
pmid
33264544
type
DERIVED