Hepatocellular Carcinoma
Conditions
Keywords
Programmed Cell Death 1 (PD1, PD-1), Programmed Cell Death Ligand 1 (PDL1, PD-L1), Programmed Cell Death Ligand 2 (PDL2, PD-L2)
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.
Interventions
BIOLOGICALPembrolizumab
Intravenous (IV) infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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 * Has a known severe hypersensitivity to pembrolizumab, its active substance and/or any of its excipients * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment * Has received prior immunotherapy including anti-programmed death-1 (anti-PD-1), anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has previously participated in clinical studies with pembrolizumab (MK-3475) * Has a known history of human immunodeficiency virus (HIV) * Has untreated active Hepatitis B virus (HBV) * For Cohort 1: has dual infection with HBV/Hepatitis C virus (HCV) or other hepatitis combinations at study entry * For Cohort 2: has dual active HBV infection (Hepatitis B surface antigen positive and/or detectable HBV deoxyribonucleic acid \[DNA\]) and HCV infection (detectable HCV ribonucleic acid \[RNA\]) at study entry * Has received a live vaccine within 30 days of planned start of study drug (Cycle 1, Day 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 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 Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD is reported. |
| Time to Progression (TTP) | 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 data. TTP per RECIST 1.1 is presented. |
| Progression-Free Survival (PFS) | 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. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. PFS is presented. |
| Duration of Response (DOR) | 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 were censored at the date of their last tumor assessment. Per RECIST 1.1, 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. The DOR per RECIST 1.1 for all participants who had a confirmed CR or PR is presented. |
| Number of Participants Who Experienced At Least One Adverse Event (AE) | 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 clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced at least one AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 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 clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued study treatment due to an AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only. |
| Overall Survival (OS) | 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. |
Participant flow
Recruitment details
This study had 2 cohorts with each cohort starting treatment at a different time period during the study. One participant allocated to Cohort 1 withdrew from the study before receiving treatment. This participant was not eligible for safety or efficacy analysis.
Pre-assignment details
Per protocol, final analyses of all outcome measures were planned to be performed during the first course of therapy and collection of adverse events and all-cause mortality were planned to be done in both first and second courses.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Participants with previously systemically treated HCC 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. | 105 |
| Cohort 2: HCC-Systemic Therapy Naïve 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. | 51 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 96 | 42 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Sponsor Decision | 8 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 2: HCC-Systemic Therapy Naïve | Total | Cohort 1: HCC-Prior Systemic Therapy With Sorafenib |
|---|---|---|---|
| Age, Continuous | 67.7 Years STANDARD_DEVIATION 10.3 | 67.6 Years STANDARD_DEVIATION 8.8 | 67.4 Years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 144 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 16 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 48 Participants | 133 Participants | 85 Participants |
| Sex: Female, Male Female | 7 Participants | 26 Participants | 19 Participants |
| Sex: Female, Male Male | 44 Participants | 130 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 94 / 105 | 42 / 51 | 2 / 4 | 0 / 1 |
| other Total, other adverse events | 96 / 104 | 46 / 51 | 4 / 4 | 0 / 1 |
| serious Total, serious adverse events | 44 / 104 | 21 / 51 | 0 / 4 | 0 / 1 |
Outcome results
Primary
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.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Objective Response Rate (ORR) | 18.3 Percentage of participants |
| Cohort 2: HCC-Systemic Therapy Naïve | Objective Response Rate (ORR) | 15.7 Percentage of participants |
Secondary
Disease Control Rate (DCR)
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 Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD is reported.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Disease Control Rate (DCR) | 61.5 Percentage of participants |
| Cohort 2: HCC-Systemic Therapy Naïve | Disease Control Rate (DCR) | 56.9 Percentage of participants |
Secondary
Duration of Response (DOR)
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 were censored at the date of their last tumor assessment. Per RECIST 1.1, 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. The DOR per RECIST 1.1 for all participants who had a confirmed CR or PR is presented.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment and who had a confirmed CR or confirmed PR during the first course of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Duration of Response (DOR) | 21.0 Months |
| Cohort 2: HCC-Systemic Therapy Naïve | Duration of Response (DOR) | 16.2 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
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 clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued study treatment due to an AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 23 Participants |
| Cohort 2: HCC-Systemic Therapy Naïve | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 8 Participants |
Secondary
Number of Participants Who Experienced At Least One Adverse Event (AE)
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 clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced at least one AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Number of Participants Who Experienced At Least One Adverse Event (AE) | 101 Participants |
| Cohort 2: HCC-Systemic Therapy Naïve | Number of Participants Who Experienced At Least One Adverse Event (AE) | 49 Participants |
Secondary
Overall Survival (OS)
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.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Overall Survival (OS) | 13.2 Months |
| Cohort 2: HCC-Systemic Therapy Naïve | Overall Survival (OS) | 16.9 Months |
Secondary
Progression-Free Survival (PFS)
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. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. PFS is presented.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Progression-Free Survival (PFS) | 4.9 Months |
| Cohort 2: HCC-Systemic Therapy Naïve | Progression-Free Survival (PFS) | 4.3 Months |
Secondary
Time to Progression (TTP)
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 data. TTP per RECIST 1.1 is presented.
Time frame: Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
Population: All participants who received at least one dose of study treatment during the first course of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HCC-Prior Systemic Therapy With Sorafenib | Time to Progression (TTP) | 4.8 Months |
| Cohort 2: HCC-Systemic Therapy Naïve | Time to Progression (TTP) | 4.4 Months |