Hepatocellular Carcinoma
Conditions
Keywords
Programmed Cell Death 1 (PD-1, PD1), Programmed Cell Death Ligand 1 (PD-L1, PDL1), Checkpoint Inhibitor, Immunotherapy, Adjuvant
Brief summary
This study will evaluate the safety and efficacy of pembrolizumab (MK-3475) versus placebo as adjuvant therapy in participants with hepatocellular carcinoma (HCC) and complete radiological response after surgical resection or local ablation. The primary hypotheses of this study are that adjuvant pembrolizumab is superior to placebo with respect to: 1) recurrence-free survival (RFS) as assessed by blinded independent central review (BICR); and 2) overall survival (OS).
Interventions
BIOLOGICALPembrolizumab
IV infusion of Pembrolizumab 200 mg.
DRUGPlacebo
IV infusion of 0.9% normal saline.
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 diagnosis of HCC by radiological criteria and/or pathological confirmation. * Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and CT or MRI of the pelvis) confirming complete radiological response ≥4 weeks after complete surgical resection or local ablation. Randomization needs to occur within 12 weeks of the date of surgical resection or local ablation. * Has no radiologic evidence of disease prior to enrollment. * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to Cycle 1, Day 1. * Has a Child-Pugh class A liver score (5 to 6 points) within 7 days prior to Cycle 1, Day 1. * Has alpha fetoprotein (AFP) concentration lower than 400 ng/mL within 28 days prior to Cycle 1, Day 1. * Has controlled hepatitis B (Hep B). * Has recovered adequately from toxicity and/or complications from the local intervention (surgical resection or local ablation) prior to starting study treatment. * If female, is not pregnant or breastfeeding, and at least one of the following conditions applies: 1) Is not a woman of childbearing potential (WOCBP); or 2) Is a WOCBP and using a contraceptive method that is highly effective or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (a WOCBP must have a negative pregnancy test within 72 hours before the first dose of study treatment). * If undergoing surgical resection, has submitted a tumor tissue sample during Screening. * Has adequate organ function.
Exclusion criteria
* Has a known additional malignancy that is progressing or has required active antineoplastic treatment (including hormonal) or surgery within the past 3 years. * Has had esophageal or gastric variceal bleeding within the last 6 months. * Has clinically apparent ascites on physical examination. * Has had clinically diagnosed hepatic encephalopathy in the last 6 months. * Has received local therapy to liver ablation other than with radiofrequency or microwave ablation. * Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. * Has an active infection requiring systemic therapy. * Has dual active Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection at study entry. * Has a known history of human immunodeficiency virus (HIV) infection. * Has known active tuberculosis (TB; Bacillus tuberculosis). * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). * Has received prior systemic anti-cancer therapy for HCC including investigational agents. * Is receiving any of the following prohibited concomitant therapies:1) Antineoplastic systemic chemotherapy or biological therapy; 2) Immunotherapy not specified in this protocol; 3) Investigational agents other than pembrolizumab; 4) Radiation therapy; 5) Oncological surgical therapy; or systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. * Has received a live vaccine within 30 days prior to the first dose of study treatment. * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to Cycle 1, Day 1. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Cycle 1, Day 1. * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. * Has an active autoimmune disease that has required systemic treatment in past 2 years. * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. * Has had an allogenic tissue/solid organ transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-Free Survival (RFS) | Up to approximately 69 months | RFS was defined as the time from randomization to first documentation of disease recurrence (local, regional, or distant) as assessed by blinded independent central review (BICR) or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death), whichever occurred first. RFS was reported for each arm. |
| Overall Survival (OS) | Up to approximately 69 months | OS was defined as the time from randomization to death due to any cause. OS was reported for each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 26 months | An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy was determined. The number of participants who experienced an AE were reported. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 23 months | An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy was determined. The number of participants who discontinued study treatment due to an AE were reported. |
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Combined Global Health Status (GHS) / Quality of Life (QoL) Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participants responded to the questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and Quality of Life ("How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1= Very poor to 7=Excellent). The combined score of GHS (Item 29) and QoL (Item 30) was computed by averaging the raw scores of the 2 items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicated a better outcome. The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score was reported. |
| Change From Baseline in EORTC QLQ-C30 Physical Functioning Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-C30 is a cancer specific health-related quality of life questionnaire. Participants responded to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score of items 1 to 5 was computed by averaging the raw scores of the 5 items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicated better physical functioning. The change from baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) combined score was reported. |
| Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-C30 is a cancer specific health-related quality of life questionnaire. The role functioning score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score was computed by averaging the raw scores of Items 6 and 7 and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicated better role functioning. The change from baseline in EORTC QLQ-C30 Role Functioning (Items 6 and 7) combined score was reported. |
| Change From Baseline in EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18) Abdominal Swelling Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The abdominal swelling scale score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores were standardized, so that scores range from 0-100. Higher scores indicated more severe symptoms/problems. Change from baseline in the EORTC QLQ-HCC18 abdominal swelling scale score was reported. |
| Change From Baseline in EORTC QLQ-HCC18 Fatigue Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The fatigue scale score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score was computed by averaging the raw scores of the items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicated more severe symptoms/problems. Change from baseline in the EORTC QLQ-HCC18 fatigue scale score was reported. |
| Change From Baseline in EORTC QLQ-HCC18 Pain Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The pain scale score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score was computed by averaging the raw scores of the items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicated more severe symptoms/problems. Change from baseline in the EORTC QLQ-HCC18 pain scale score was reported. |
| Change From Baseline in Visual Analogue Scale (VAS) Score on the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score | Baseline and up to approximately 120 weeks | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The VAS is a component of the EQ-5D-5L that asked participants to rate their overall health on a vertical visual analogue scale, with the scale's ends labelled 'The best health you can imagine' (equivalent to a score of 0) and 'The worst health you can imagine' (equivalent to a score of 100). |
| Time to Deterioration (TTD) in the EORTC QLQ-C30 Combined GHS / QoL Scale Score | Baseline and up to approximately 120 weeks | EORTC QLQ-C30 is a questionnaire to assess QoL of cancer patients. Participants responded to questions on GHS ("How would you rate your overall health during the past week?") and QoL ("How would you rate your overall QoL during the past week?") were scored on a 7-point scale (1= Very poor to 7=Excellent). The combined score of GHS (Item 29) and QoL (Item 30) was computed by averaging raw scores of the 2 items and applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicated a better outcome. TTD was defined as the time from baseline to first onset of ≥10-point negative change (decrease) from baseline in GHS-QoL combined score. A longer TTD indicated a better outcome. |
| TTD in the EORTC QLQ-C30 Physical Functioning Scale Score | Baseline and up to approximately 120 weeks | EORTC QLQ-C30 is a questionnaire to assess the overall QoL of cancer patients. Participants responded to 5 questions about their physical functioning (Items 1 to 5) are scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score of items 1 to 5 was computed by averaging the raw scores of the 5 items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicated a better outcome. TTD was defined as the time from baseline to first onset of ≥10-point negative change (decrease) from baseline in physical functioning (Items 1 to 5). A longer TTD indicated a better outcome. |
| TTD in the EORTC QLQ-C30 Role Functioning Scale Score | Baseline and up to approximately 120 weeks | EORTC QLQ-C30 is a questionnaire to assess the overall QoL of cancer patients. Participants responded to questions about their role functioning (Items 6 and 7) are scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score of Items 6 and 7 was computed by averaging the raw scores of the items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicated a better outcome. TTD was defined as the time from baseline to first onset of ≥10-point negative change (decrease) from baseline in physical functioning (Items 6 and 7). A longer TTD indicated a better outcome. |
| TTD in the EORTC QLQ-HCC18 Abdominal Swelling Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The abdominal swelling scale score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores were standardized, so that scores range from 0-100. Higher scores indicated more severe symptoms/problems. The TTD in EORTC QLQ-HCC18 abdominal swelling scale score was reported, defined as the time to first onset of a ≥10 point decrease from baseline. |
| TTD in the EORTC QLQ-HCC18 Fatigue Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The fatigue scale score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score was computed by averaging the raw scores of the items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicated more severe symptoms/problems. The TTD in EORTC QLQ-HCC18 fatigue scale score was reported, defined as the time to first onset of a ≥10 point decrease from baseline. |
| TTD in the EORTC QLQ-HCC18 Pain Scale Score | Baseline and up to approximately 120 weeks | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The pain scale score was based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score was computed by averaging the raw scores of the items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicated more severe symptoms/problems. The TTD in EORTC QLQ-HCC18 pain scale score was reported, defined as the time to first onset of a ≥10 point decrease from baseline. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Denmark, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Malaysia, New Zealand, Norway, Poland, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
Participants at least 18 years of age with hepatocellular carcinoma (HCC) and who had complete radiological response after surgical resection or local ablation were recruited.
Pre-assignment details
Of 1313 participants screened, 959 participants were randomized 1:1 to receive either pembrolizumab or placebo.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.2 Years STANDARD_DEVIATION 11.1 |
| Alpha Fetoprotein (AFP) at Initial Diagnosis Prior to Resection or Ablation <200 ng/mL | 368 Participants |
| Alpha Fetoprotein (AFP) at Initial Diagnosis Prior to Resection or Ablation >=200 ng/mL | 91 Participants |
| Alpha Fetoprotein (AFP) at Initial Diagnosis Prior to Resection or Ablation Missing | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 891 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants |
| Prior Local Therapy Ablation | 114 Participants |
| Prior Local Therapy Resection | 421 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 268 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 196 Participants |
| Recurrence Risk Group High | 693 Participants |
| Recurrence Risk Group Intermediate | 199 Participants |
| Recurrence Risk Group Very High | 30 Participants |
| Region of Enrolling Site Asia without Japan | 207 Participants |
| Region of Enrolling Site Non-Asia and Japan | 286 Participants |
| Sex: Female, Male Female | 101 Participants |
| Sex: Female, Male Male | 759 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 109 / 476 | 109 / 483 |
| other Total, other adverse events | 350 / 471 | 278 / 482 |
| serious Total, serious adverse events | 103 / 471 | 59 / 482 |
Outcome results
None listed