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NCT02702414

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

Completed Phase 2 Results posted Last updated 4 September 2024
What this trial tests

Phase 2 trial testing Pembrolizumab in Hepatocellular Carcinoma in 156 participants. Completed in 29 September 2023.

Timeline
31 May 2016
Primary endpoint
19 January 2021
29 September 2023

Quick facts

Lead sponsorMerck Sharp & Dohme LLC
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment156
Start date31 May 2016
Primary completion19 January 2021
Estimated completion29 September 2023

Drugs / interventions tested

Conditions studied

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Hepatocellular Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Objective Response Rate (ORR) Primary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

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.

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib18.311.4 – 27.1
Cohort 2: HCC-Systemic Therapy Naïve15.77.0 – 28.6
Duration of Response (DOR) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

DOR was determined in participants who demonstrated a confirmed Complete Response (CR: disappearance of all target and non-target lesions) or Partial Response (PR: ≥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. DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed, started a new anti-cancer therapy, been lost to follow-up, or died at the time of analysis w

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib21.010.7 – NA
Cohort 2: HCC-Systemic Therapy Naïve16.23.1 – NA
Disease Control Rate (DCR) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

DCR was defined as the percentage of participants who had a CR (disappearance of all target and non-target lesions), PR (at least a 30% decrease in the sum of diameters of target and non-target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions.\]). CR, PR, and SD were evaluated per Response Evaluatio

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib61.551.5 – 70.9
Cohort 2: HCC-Systemic Therapy Naïve56.942.2 – 70.7
Time to Progression (TTP) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

TTP was defined as the time from the first dose to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. If there was no documented disease progression, TTP was censored at last tumor assessment date. The TTP was analyzed using the product-limit (Kaplan-Meier) method for censored da

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib4.83.9 – 7.0
Cohort 2: HCC-Systemic Therapy Naïve4.42.5 – 8.6
Progression-Free Survival (PFS) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

PFS was defined as the time from the first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. If there was no disease progression or death, participants were censored at the date of their last disease assessment. T

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib4.93.5 – 6.7
Cohort 2: HCC-Systemic Therapy Naïve4.32.1 – 7.8
Overall Survival (OS) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

OS was determined for all participants and was defined as the time from the first dose to death due to any cause. Participants were censored at the last known alive date. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The OS is presented.

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib13.29.7 – 15.3
Cohort 2: HCC-Systemic Therapy Naïve16.98.3 – 23.1
Number of Participants Who Experienced At Least One Adverse Event (AE) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clini

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib101
Cohort 2: HCC-Systemic Therapy Naïve49
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) Secondary · Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clini

GroupValue95% CI
Cohort 1: HCC-Prior Systemic Therapy With Sorafenib23
Cohort 2: HCC-Systemic Therapy Naïve8

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 87 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy With Sorafenib-First Course
Serious: 44/104 (42%)
Deaths: 94/105
Cohort 2: HCC-Systemic Therapy Naïve-First Course
Serious: 21/51 (41%)
Deaths: 42/51
Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy With Sorafenib-Second Course
Serious: 0/4 (0%)
Deaths: 2/4
Cohort 2: HCC-Systemic Therapy Naïve-Second Course
Serious: 0/1 (0%)
Deaths: 0/1

Serious adverse events (80 terms)

ReactionSystemCohort 1: Hepatocellular C…Cohort 2: HCC-Systemic The…Cohort 1: Hepatocellular C…Cohort 2: HCC-Systemic The…
AscitesGastrointestinal disorders
Aspartate aminotransferase increasedInvestigations
AnaemiaBlood and lymphatic system disorders
Upper gastrointestinal haemorrhageGastrointestinal disorders
SepsisInfections and infestations
Adrenal insufficiencyEndocrine disorders
Oesophageal varices haemorrhageGastrointestinal disorders
Jaundice cholestaticHepatobiliary disorders
PneumoniaInfections and infestations
Alanine aminotransferase increasedInvestigations
HyperkalaemiaMetabolism and nutrition disorders
EncephalopathyNervous system disorders
Renal failureRenal and urinary disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Hypovolaemic shockVascular disorders
Acute myocardial infarctionCardiac disorders
Atrioventricular block second degreeCardiac disorders
Cardiac failureCardiac disorders
Cardiogenic shockCardiac disorders
Chronic left ventricular failureCardiac disorders
MyocarditisCardiac disorders
Ventricular fibrillationCardiac disorders
HypophysitisEndocrine disorders
Retinal vein occlusionEye disorders
Abdominal painGastrointestinal disorders
Other adverse events (51 terms — click to expand)

ReactionSystemCohort 1: Hepatocellular C…Cohort 2: HCC-Systemic The…Cohort 1: Hepatocellular C…Cohort 2: HCC-Systemic The…
FatigueGeneral disorders
PruritusSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
NauseaGastrointestinal disorders
Oedema peripheralGeneral disorders
ArthralgiaMusculoskeletal and connective tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
ConstipationGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
Abdominal painGastrointestinal disorders
AstheniaGeneral disorders
Decreased appetiteMetabolism and nutrition disorders
RashSkin and subcutaneous tissue disorders
Alanine aminotransferase increasedInvestigations
AscitesGastrointestinal disorders
AnaemiaBlood and lymphatic system disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Abdominal pain upperGastrointestinal disorders
VomitingGastrointestinal disorders
Blood bilirubin increasedInvestigations
HypothyroidismEndocrine disorders
Back painMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
InsomniaPsychiatric disorders
Blood alkaline phosphatase increasedInvestigations
Weight decreasedInvestigations
Muscle spasmsMusculoskeletal and connective tissue disorders
Productive coughRespiratory, thoracic and mediastinal disorders
Night sweatsSkin and subcutaneous tissue disorders
Dry mouthGastrointestinal disorders
PyrexiaGeneral disorders
BronchitisInfections and infestations
NasopharyngitisInfections and infestations
HypophosphataemiaMetabolism and nutrition disorders
DizzinessNervous system disorders
DyspepsiaGastrointestinal disorders
Mucosal inflammationGeneral disorders
PneumoniaInfections and infestations
RhinitisInfections and infestations

Most-reported serious reactions: Ascites, Aspartate aminotransferase increased, Anaemia, Upper gastrointestinal haemorrhage, Sepsis, Adrenal insufficiency, Oesophageal varices haemorrhage, Jaundice cholestatic.

Data from ClinicalTrials.gov NCT02702414 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. A global view of hepatocellular carcinoma: trends, risk, prevention and management.
    Yang JD, Hainaut P, Gores GJ, Amadou A, et al · · 2019 · cited 3157× · PMID 31439937 · DOI 10.1038/s41575-019-0186-y
  2. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
    Zhu AX, Finn RS, Edeline J, Cattan S, et al · · 2018 · cited 1917× · PMID 29875066 · DOI 10.1016/s1470-2045(18)30351-6
  3. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
    Omata M, Cheng AL, Kokudo N, Kudo M, et al · · 2017 · cited 1607× · PMID 28620797 · DOI 10.1007/s12072-017-9799-9
  4. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).
    Cohen EEW, Bell RB, Bifulco CB, Burtness B, et al · · 2019 · cited 528× · PMID 31307547 · DOI 10.1186/s40425-019-0662-5
  5. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers.
    Tang Q, Chen Y, Li X, Long S, et al · · 2022 · cited 360× · PMID 36177034 · DOI 10.3389/fimmu.2022.964442
  6. Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review.
    Oura K, Morishita A, Tani J, Masaki T. · · 2021 · cited 340× · PMID 34071550 · DOI 10.3390/ijms22115801
  7. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells.
    Ruf B, Heinrich B, Greten TF. · · 2021 · cited 247× · PMID 33235387 · DOI 10.1038/s41423-020-00572-w
  8. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy.
    Li Q, Han J, Yang Y, Chen Y. · · 2022 · cited 173× · PMID 36601120 · DOI 10.3389/fimmu.2022.1070961

Verify or expand the search:

Other trials of Pembrolizumab

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Trials by the same sponsor.

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