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)

NCT02563002 | Completed Phase 3 Results DMC FDA Drug

• 5 other identifiers: 3475-177163238MK-3475-177KEYNOTE-1772015-002024-89
• Study Type: interventional
• Target: 307
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Colorectal Carcinoma

Keywords

Programmed Cell Death Receptor 1 (PD-1); Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1)

Outcome Measures

Primary Outcomes (2)

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

  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.

  Up to approximately 59 months

• Overall Survival (OS)

  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.

  Up to approximately 59 months

Secondary Outcomes (3)

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

  Up to approximately 59 months

• Number of Participants Who Experienced an Adverse Event (AE)

  Up to approximately 59 months

• Number of Participants Who Discontinued Study Treatment Due to an AE

  Up to approximately 59 months

Study Arms (2)

Pembrolizumab

EXPERIMENTAL

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).

Biological: Pembrolizumab

Standard of Care (SOC)

ACTIVE COMPARATOR

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).

Drug: mFOLFOX6; Drug: FOLFIRI; Biological: Pembrolizumab; Biological: Bevacizumab; Biological: Cetuximab

Interventions

mFOLFOX6 DRUG

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

Standard of Care (SOC)

FOLFIRI DRUG

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

Standard of Care (SOC)

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, SCH 900475, KEYTRUDA®

Pembrolizumab; Standard of Care (SOC)

Bevacizumab BIOLOGICAL

IV infusion

Standard of Care (SOC)

Cetuximab BIOLOGICAL

IV infusion

Standard of Care (SOC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (4)

• 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 DERIVED

• 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 DERIVED

• 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 DERIVED

• 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 DERIVED

Related Links

• Merck Clinical Trial Information
• Plain Language Summary

MeSH Terms

Conditions

Colorectal Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

IFL protocol; pembrolizumab; Bevacizumab; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@msd.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2015
• First Posted: September 29, 2015
• Study Start: November 30, 2015
• Primary Completion: February 19, 2021
• Study Completion: July 17, 2023
• Last Updated: October 3, 2024
• Results First Posted: March 16, 2022

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share