Carcinoma, Hepatocellular
Conditions
Keywords
Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (PD-L1), Programmed Cell Death Receptor Ligand 2 (PD-L2), PD1, PD-1, PDL1, PD-L1, PDL2
Brief summary
The purpose of this study is to determine the efficacy and safety of pembrolizumab or placebo given with best supportive care (BSC) in Asian participants with previously systemically treated advanced hepatocellular carcinoma (HCC). The primary hypothesis of this study is that overall survival is prolonged in participants who receive pembrolizumab compared to those who receive placebo.
Interventions
BIOLOGICALpembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
DRUGplacebo
Normal saline solution administered as an IV infusion Q3W
OTHERbest supportive care (BSC)
BSC will include pain management and management of other potential complications including ascites per local standards of care.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 A liver score within 7 days prior to first dose of study medication * Has a life expectancy of \>3 months * Has at least one measurable lesion based on RECIST version 1.1 as determined by investigator. * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 7 days prior to receiving the first dose of study medication. * Has documented objective radiographic progression during or after treatment with sorafenib or oxaliplatin-based chemotherapy, or else intolerance to sorafenib or oxaliplatin-based chemotherapy * Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy * Female and male participants of reproductive potential must agree to use adequate contraception starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication
Exclusion criteria
* Is currently participating or has participated in a study with an investigational agent or using an investigational device within 4 weeks of the first dose of study medication * Has received sorafenib or oxaliplatin-based chemotherapy within 14 days of first dose of study medication * 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 branch (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 or oxaliplatin-based chemotherapy, prior to start of study medication * Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment. * 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 medication * 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 medication * Has had major surgery to liver or other site within 4 weeks prior to the first dose of study medication * Has had a minor surgery ≤7 days prior to the first dose of study medication * Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to study start * Has a diagnosed additional malignancy within 3 years prior to first dose of study medication with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers * Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis * Has an active infection requiring systemic therapy * Is pregnant or breast feeding or expecting to conceive or father starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication * Has received prior immunotherapy with an anti-Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (anti-PD-L1), or anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) or has previously participated in clinical studies with pembrolizumab * Has a known history of human immunodeficiency virus (HIV) * Has untreated active Hepatitis B * Has Hepatitis C in which participants received therapy for HCV \<4 weeks prior to receiving pembrolizumab * Has received a live vaccine within 30 days prior to the first dose of study therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 4 years | OS is the time from randomization to death due to any cause, based on the Kaplan-Meier method for censored data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 4 years | ORR is the percentage of participants who achieve complete response (CR) or partial response (PR) with confirmation per RECIST 1.1 by BICR. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions. |
| Duration Of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 4 years | DOR is the time from first documented evidence of CR or PR per RECIST 1.1 by BICR until disease progression per RECIST 1.1 by BICR or death, based on Kaplan-Meier method for censored data. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions. |
| Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 4 years | DCR is the percentage of participants who achieve CR, PR, or stable disease (SD) for ≥5 weeks prior to evidence of disease progression per RECIST 1.1 by BICR. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions. |
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 4 years | PFS is the time from randomization to first documented disease progression or death due to any cause per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) based on the Kaplan-Meier method for censored data. |
| Number of Participants Who Experienced At Least One Adverse Event (AE) | Up to approximately 30 months. | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 27 months. | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. |
| Time To Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 4 years | TTP is the time from randomization to first documented disease progression per RECIST 1.1 by BICR, based on Kaplan-Meier method for censored data. |
Countries
China, Hong Kong, Malaysia, South Korea, Taiwan
Participant flow
Recruitment details
Male and female participants at least 18 years of age with advanced hepatocellular carcinoma (HCC) after progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy with no curative option were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + BSC Participants received 200 mg pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus BSC. | 300 |
| Placebo + BSC Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus BSC. | 153 |
| Total | 453 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 269 | 145 |
| Overall Study | Sponsor Decision | 29 | 7 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab + BSC | Placebo + BSC | Total |
|---|---|---|---|
| Age, Continuous | 54.6 Years STANDARD_DEVIATION 12.1 | 52.0 Years STANDARD_DEVIATION 12.9 | 53.7 Years STANDARD_DEVIATION 12.4 |
| Alpha-Fetoprotein (α-Fetoprotein) < 200 ng/mL | 131 Participants | 75 Participants | 206 Participants |
| Alpha-Fetoprotein (α-Fetoprotein) ≥ 200 ng/mL | 169 Participants | 78 Participants | 247 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 300 Participants | 153 Participants | 453 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Macrovascular Invasion No | 267 Participants | 136 Participants | 403 Participants |
| Macrovascular Invasion Yes | 33 Participants | 17 Participants | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 300 Participants | 153 Participants | 453 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region China | 255 Participants | 132 Participants | 387 Participants |
| Region Ex-China | 45 Participants | 21 Participants | 66 Participants |
| Sex: Female, Male Female | 43 Participants | 27 Participants | 70 Participants |
| Sex: Female, Male Male | 257 Participants | 126 Participants | 383 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 263 / 300 | 146 / 153 | 8 / 12 |
| other Total, other adverse events | 272 / 299 | 135 / 153 | 12 / 12 |
| serious Total, serious adverse events | 76 / 299 | 31 / 153 | 1 / 12 |
Outcome results
Primary
Overall Survival (OS)
OS is the time from randomization to death due to any cause, based on the Kaplan-Meier method for censored data.
Time frame: Up to approximately 4 years
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + BSC | Overall Survival (OS) | 14.6 Months |
| Placebo + BSC | Overall Survival (OS) | 13.0 Months |
p-value: 0.01895% CI: [0.63, 0.99]One-sided p-value
Secondary
Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
DCR is the percentage of participants who achieve CR, PR, or stable disease (SD) for ≥5 weeks prior to evidence of disease progression per RECIST 1.1 by BICR. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions.
Time frame: Up to approximately 4 years
Population: All randomized participants based on the treatment group to which they were randomized, who achieved CR, PR, or SD for ≥5 weeks prior to evidence of disease progression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + BSC | Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 52.7 Percentage of participants |
| Placebo + BSC | Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 47.7 Percentage of participants |
Comparison: Difference in % vs Placebop-value: 0.1328195% CI: [-4.1, 14.8]One-sided p-value for testing
Secondary
Duration Of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
DOR is the time from first documented evidence of CR or PR per RECIST 1.1 by BICR until disease progression per RECIST 1.1 by BICR or death, based on Kaplan-Meier method for censored data. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions.
Time frame: Up to approximately 4 years
Population: All randomized participants with CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + BSC | Duration Of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 23.9 Months |
| Placebo + BSC | Duration Of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 5.6 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy.
Time frame: Up to approximately 27 months.
Population: Randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + BSC | Number of Participants Who Discontinued Study Treatment Due to an AE | 38 Participants |
| Placebo + BSC | Number of Participants Who Discontinued Study Treatment Due to an AE | 13 Participants |
Secondary
Number of Participants Who Experienced At Least One Adverse Event (AE)
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy.
Time frame: Up to approximately 30 months.
Population: Randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + BSC | Number of Participants Who Experienced At Least One Adverse Event (AE) | 283 Participants |
| Placebo + BSC | Number of Participants Who Experienced At Least One Adverse Event (AE) | 147 Participants |
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
ORR is the percentage of participants who achieve complete response (CR) or partial response (PR) with confirmation per RECIST 1.1 by BICR. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions.
Time frame: Up to approximately 4 years
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + BSC | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 12.7 Percentage of participants |
| Placebo + BSC | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 1.3 Percentage of participants |
Comparison: Difference in % vs Placebop-value: 0.0000495% CI: [6.7, 16]One-sided p-value for testing
Secondary
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
PFS is the time from randomization to first documented disease progression or death due to any cause per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) based on the Kaplan-Meier method for censored data.
Time frame: Up to approximately 4 years
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + BSC | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 2.6 Months |
| Placebo + BSC | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 2.3 Months |
p-value: 0.003295% CI: [0.6, 0.92]One-sided p-value
Secondary
Time To Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
TTP is the time from randomization to first documented disease progression per RECIST 1.1 by BICR, based on Kaplan-Meier method for censored data.
Time frame: Up to approximately 4 years
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + BSC | Time To Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 2.7 Months |
| Placebo + BSC | Time To Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 1.7 Months |
p-value: 0.001995% CI: [0.58, 0.9]One-sided p-value