Study of Pembrolizumab (MK-3475) vs. Best Supportive Care in Participants With Previously Systemically Treated Advanced Hepatocellular Carcinoma (MK-3475-240/KEYNOTE-240)

NCT02702401 | Completed Phase 3 Results DMC

• 5 other identifiers: 3475-240163456MK-3475-240KEYNOTE-2402015-004567-36
• Study Type: interventional
• Target: 413
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a study of pembrolizumab (MK-3475) in participants with previously systemically treated advanced hepatocellular carcinoma (HCC). The primary objectives of this study are to determine 1) Progression-Free Survival (PFS) and 2) Overall Survival (OS) of pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC. The primary hypotheses of this study are: 1) pembrolizumab plus BSC prolongs PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed by Blinded Independent Central Review compared to placebo plus BSC, and 2) pembrolizumab plus BSC improves OS compared with placebo plus BSC. Effective with Amendment 4: 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 1 Ligand 1 (PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Outcome Measures

Primary Outcomes (2)

• Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. Final analyses for PFS was performed for the first pembrolizumab course at protocol specified cut off of 26-Mar-2018.

  Through database cutoff date of 26-Mar-2018 (Up to approximately 21 months)

• Overall Survival (OS)

  OS was determined for all participants and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last follow-up. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. Final analyses for OS was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019.

  Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Secondary Outcomes (6)

• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

• Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

• Time to Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

• Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  From time of first documented evidence of CR or PR through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

• Number of Participants Who Experienced At Least One Adverse Event (AE)

  Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Study Arms (2)

Pembrolizumab+Best Supportive Care

EXPERIMENTAL

Participants receive a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).

Biological: Pembrolizumab; Other: Best Supportive Care

Placebo+Best Supportive Care

PLACEBO COMPARATOR

Participants receive a placebo IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.

Drug: Placebo; Other: Best Supportive Care

Interventions

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab+Best Supportive Care

Placebo DRUG

0.90% w/v sodium chloride IV infusion

Placebo+Best Supportive Care

Best Supportive Care OTHER

Best supportive care will include pain management and management of other potential complications including ascites per local standards of care.

Pembrolizumab+Best Supportive Care; Placebo+Best Supportive Care

Eligibility Criteria

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

You may qualify if:

• Has a 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 at least one measurable lesion based on 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.
• Has documented objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib.
• Participants with chronic infection by Hepatitis C Virus (HCV) who are treated (successfully or treatment failure) or untreated are allowed on study. In addition, participants with successful HCV treatment are allowed as long as there are ≥4 weeks between achieving sustained viral response (SVR12) and start of study drug.
• Has controlled Hepatitis B Virus (HBV) infection.
• Is willing to use an adequate method of contraception for the course of the study through at least 120 days or longer based on local regulation 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, or has participated in a study of an investigational agent and received study drug, herbal/complementary oral or IV medicine, or used an investigational device within 4 weeks of the first dose of study drug. Participants must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from adverse events (AEs) due to any prior therapy.
• 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. Note: ascites detectable on imaging studies only ARE allowed.
• Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging.
• Has had clinically diagnosed hepatic encephalopathy in the last 6 months.
• Has had a solid organ or hematologic transplant.
• Has had prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib, prior to the start of study drug.
• Has a known severe hypersensitivity (≥Grade 3) to pembrolizumab, its active substance and/or any of its excipients.
• 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 received locoregional therapy to liver (transcatheter chemoembolization \[TACE\], transcatheter embolization \[TAE\], hepatic arterial infusion \[HAI\], radiation, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug.
• Has had major surgery to liver or other site within 4 weeks prior to the first dose of study drug.
• Has had minor surgery (i.e., simple excision, tooth extraction) ≤7 days prior to the first dose of study drug (Cycle 1, Day 1).
• Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to starting study drug.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (4)

• Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL; KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020 Jan 20;38(3):193-202. doi: 10.1200/JCO.19.01307. Epub 2019 Dec 2.

  PMID: 31790344 RESULT

• 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

• Finn RS, Gu K, Chen X, Merle P, Lee KH, Bouattour M, Cao P, Wang W, Cheng AL, Zhu L, Lim HY, Kudo M, Pan Y, Chang TT, Edeline J, Li W, Yang P, Li C, Li J, Siegel AB, Qin S. Second-line pembrolizumab for advanced HCC: Meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies. JHEP Rep. 2025 Feb 4;7(6):101350. doi: 10.1016/j.jhepr.2025.101350. eCollection 2025 Jun.

  PMID: 40486134 DERIVED

• Vogel A, Merle P, Verslype C, Finn RS, Zhu AX, Cheng AL, Chan SL, Yau T, Ryoo BY, Knox J, Daniele B, Qin S, Wei Z, Miteva Y, Malhotra U, Siegel AB, Kudo M. ALBI score and outcomes in patients with hepatocellular carcinoma: post hoc analysis of the randomized controlled trial KEYNOTE-240. Ther Adv Med Oncol. 2021 Sep 30;13:17588359211039928. doi: 10.1177/17588359211039928. eCollection 2021.

  PMID: 34616489 DERIVED

Related Links

• Merck Oncology 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 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• 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 26, 2016
• Primary Completion: January 2, 2019
• Study Completion: September 22, 2021
• Last Updated: September 29, 2022
• Results First Posted: February 17, 2020

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share