Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224)

NCT02702414 | Completed Phase 2 Results DMC FDA Drug

• 5 other identifiers: 3475-224MK-3475-224KEYNOTE-2241634342015-004566-28
• Study Type: interventional
• Target: 156
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a efficacy and safety study of pembrolizumab (MK-3475, KEYTRUDA®) as monotherapy in participants with hepatocellular carcinoma (HCC) in two cohorts: participants with advanced HCC and with no curative option after disease progression on sorafenib or intolerance of sorafenib (Cohort 1) or who had not received treatment for systemic disease (Cohort 2). Study participants may receive pembrolizumab once every 3 weeks for up to 35 initial cycles (up to approximately 2 years) and a potential additional 17 cycles in a re-treatment phase (approximately an additional 1 year of treatment) . The primary objective of this study is to determine the Objective Response Rate (ORR) of pembrolizumab given as monotherapy in participants with HCC. Effective with Amendment 7: Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.

Conditions

Hepatocellular Carcinoma

Keywords

Programmed Cell Death 1 (PD1, PD-1); Programmed Cell Death Ligand 1 (PDL1, PD-L1); Programmed Cell Death Ligand 2 (PDL2, PD-L2)

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  ORR was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target and non-target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target and non-target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered non-responders. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented.

  Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

Secondary Outcomes (7)

• Duration of Response (DOR)

  Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

• Disease Control Rate (DCR)

  Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

• Time to Progression (TTP)

  Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

• Progression-Free Survival (PFS)

  Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

• Overall Survival (OS)

  Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

Study Arms (2)

Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib

EXPERIMENTAL

Participants with previously systemically treated HCC received a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

Biological: Pembrolizumab

Cohort 2: HCC-Systemic Therapy Naïve

EXPERIMENTAL

Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

Biological: Pembrolizumab

Interventions

Pembrolizumab BIOLOGICAL

Intravenous (IV) infusion

Also known as: MK-3475, KEYTRUDA®

Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib; Cohort 2: HCC-Systemic Therapy Naïve

Eligibility Criteria

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

You may qualify if:

• For Cohort 1: has histologically or cytologically confirmed diagnosis of HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) based on pathology report
• For Cohort 2: has an HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)
• Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach
• Has a Child-Pugh Class A liver score within 7 days of first dose of study drug
• Has a predicted life expectancy \>3 months
• Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as confirmed by the blinded central imaging vendor
• Has a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 7 days of first dose of study drug
• For Cohort 1: has documented objective radiographic progression after stopping treatment with sorafenib or else intolerance to sorafenib
• Is willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug (male and female participants of childbearing potential)
• Demonstrates adequate organ function

You may not qualify if:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, herbal/complementary oral or intravenous (IV) medicine, or used an investigational device within 4 weeks of the first dose of study drug. Participant must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from adverse events due to any prior therapy
• For Cohort 1: has received sorafenib within 14 days of first dose of study drug
• Has had esophageal or gastric variceal bleeding within the last 6 months
• Has clinically apparent ascites on physical examination
• Has portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging
• Has had encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their encephalopathy are not allowed
• Had a solid organ or hematologic transplant
• For Cohort 1: had prior systemic therapy for HCC other than sorafenib, or intercurrent local therapy to the liver tumor between sorafenib and study drug
• For Cohort 2: had prior systemic therapy in the advanced disease setting
• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs)
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a diagnosed additional malignancy within 5 years for Cohort 1 and 3 years for Cohort 2 prior to first dose of study treatment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers
• Has radiographically detectable central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has evidence or history of interstitial lung disease or active noninfectious pneumonitis
• Has an active infection requiring systemic therapy

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (5)

• Chan SL, Finn RS, Edeline J, Ogasawara S, Knox JJ, Daniele B, Ryoo BY, Merle P, Bouattour M, Lim HY, Chao Y, Yau T, Haber BA, Malhotra U, Siegel AB, Liu CC, Kudo M, Cheng AL. Effect of pembrolizumab on viral hepatitis load and transaminases in advanced hepatocellular carcinoma. Ann Hepatol. 2025 Dec 24;31(1):102169. doi: 10.1016/j.aohep.2025.102169. Online ahead of print.

  PMID: 41453647 DERIVED

• Zhou X, Cao J, Topatana W, Xie T, Chen T, Hu J, Li S, Juengpanic S, Lu Z, Zhang B, Wang K, Feng X, Shen J, Chen M. Evaluation of PD-L1 as a biomarker for immunotherapy for hepatocellular carcinoma: systematic review and meta-analysis. Immunotherapy. 2023 Apr;15(5):353-365. doi: 10.2217/imt-2022-0168. Epub 2023 Feb 27.

  PMID: 36852452 DERIVED

• Verset G, Borbath I, Karwal M, Verslype C, Van Vlierberghe H, Kardosh A, Zagonel V, Stal P, Sarker D, Palmer DH, Vogel A, Edeline J, Cattan S, Kudo M, Cheng AL, Ogasawara S, Daniele B, Chan SL, Knox JJ, Qin S, Siegel AB, Chisamore M, Hatogai K, Wang A, Finn RS, Zhu AX. Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Clin Cancer Res. 2022 Jun 13;28(12):2547-2554. doi: 10.1158/1078-0432.CCR-21-3807.

  PMID: 35421228 DERIVED

• Kudo M, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer DH, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Yau T, Gurary EB, Siegel AB, Wang A, Cheng AL, Zhu AX; KEYNOTE-224 Investigators. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur J Cancer. 2022 May;167:1-12. doi: 10.1016/j.ejca.2022.02.009. Epub 2022 Mar 29.

  PMID: 35364421 DERIVED

• Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3.

  PMID: 29875066 DERIVED

Related Links

• Merck Clinical Trials Information

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Results Point of Contact

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

ClinicalTrialsDisclosure@merck.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 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2016
• First Posted: March 8, 2016
• Study Start: May 31, 2016
• Primary Completion: January 19, 2021
• Study Completion: September 29, 2023
• Last Updated: September 4, 2024
• Results First Posted: April 4, 2022

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share