Hepatocellular Carcinoma (HCC)
Conditions
Keywords
Advanced liver cancer, RATIONALE-208
Brief summary
This study investigated the efficacy, safety, and pharmacokinetics of the anti-PD-1 monoclonal antibody BGB-A317 in participants with previously treated hepatocellular unresectable carcinoma.
Interventions
DRUGTislelizumab
Administered intravenously
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Histologically confirmed HCC 2. Participants with Barcelona Clinic Liver Cancer (BCLC) Stage C, or BCLC stage B not amenable to locoregional therapy or relapsed after locoregional therapy, and not amenable to a curative treatment approach 3. Has received at least 1 line of systemic therapy for unresectable HCC 4. Has at least 1 measurable lesion as defined per RECIST v1.1 5. Child-Pugh score A 6. Easter Cooperative Oncology Group (ECOG) Performance Status ≤ 1 7. Adequate organ function Key
Exclusion criteria
1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC histology 2. Prior therapies targeting PD-1 or PD-L1 3. Has known brain or leptomeningeal metastasis 4. Tumor thrombus involving main trunk of portal vein or inferior vena cava 5. Loco-regional therapy to the liver within 4 weeks before enrollment 6. Medical history of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, or acute lung diseases 7. Has received: 1. Within 28 days or 5 half-lives (whichever is shorter) of the first study drug administration: any chemotherapy, immunotherapy (eg, interleukin, interferon, thymoxin) or any investigational therapies 2. Within 14 days of the first study drug administration: sorafenib, regorafenib, or any Chinese herbal medicine or Chinese patent medicines used to control cancer 8. Active autoimmune diseases or history of autoimmune diseases that may relapse 9. Participant with any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 14 days before study drug administration NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Assessed by Independent Review Committee (IRC) | From date of first dose to primary analysis data cut-off date of 30-June-2021 (up to approximately 3 years and 3 months) | ORR is defined as the percentage of participants with complete response (CR) and partial response (PR) as the best overall response, as determined by an IRC using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) Assessed by IRC | From date of first dose to end of study (up to approximately 4 years and 3 months) | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the IRC using RECIST v1.1 |
| DOR Event-Free Rate Assessed by IRC | From date of first dose to end of study (up to approximately 4 years and 3 months); Months 12 and 24 reported | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the IRC using RECIST v1.1. The Kaplan-Meier method was used to estimate the percentage of participants who were event-free for progression or death at 12 and 24 months with 95% confidence intervals estimated using Greenwood's formula. |
| DOR Assessed by Investigator | From date of first dose to end of study (up to approximately 4 years and 3 months) | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the investigator using RECIST v1.1 |
| DOR Event-Free Rate Assessed by Investigator | From date of first dose to end of study (up to approximately 4 years and 3 months); Months 12 and 24 reported | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the investigator using RECIST v1.1. The Kaplan-Meier method was used to estimate the percentage of participants who were event-free for progression or death at 12 and 24 months with 95% confidence intervals estimated using Greenwood's formula. |
| Progression-free Survival (PFS) Assessed by IRC | From date of first dose to end of study (up to approximately 4 years and 3 months) | PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by the IRC using RECIST v1.1 |
| PFS Assessed by Investigator | From date of first dose to end of study (up to approximately 4 years and 3 months) | PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by the investigator using RECIST v1.1 |
| Overall Survival (OS) | From date of first dose to end of study (up to approximately 4 years and 3 months) | OS is defined as the time from first study drug administration to the date of death due to any cause |
| ORR Assessed by Investigator | From date of first dose to end of study (up to approximately 4 years and 3 months) | ORR is defined as the percentage of participants with CR and PR as the best overall response, as determined by investigator assessment using RECIST v1.1. CR is defined as disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. |
| DCR Assessed by Investigator | From date of first dose to end of study (up to approximately 4 years and 3 months) | DCR is defined as the percentage of participants whose best overall response is CR, PR, or stable disease (SD) as assessed by the investigator using RECIST v1.1 |
| Clinical Benefit Rate (CBR) Assessed by IRC | From date of first dose to end of study (up to approximately 4 years and 3 months) | CBR is defined as the percentage of participants who have CR, PR, or SD of ≥ 24 weeks in duration as assessed by the IRC using RECIST v1.1 |
| CBR Assessed by Investigator | From date of first dose to end of study (up to approximately 4 years and 3 months) | CBR is defined as the percentage of participants who have CR, PR, or SD of ≥ 24 weeks in duration as assessed by the investigator using RECIST v1.1 |
| European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) Visual Analogue Score (VAS) | Baseline to Cycle 6 Day 1 and Cycle 12 Day 1 (each cycle is 21 days) | Mean change from baseline in EQ-5D-5L VAS. The EQ-5D-5L measures health outcomes using a VAS to record a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes. |
| European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | Baseline to Cycle 6 Day 1 and Cycle 12 Day 1 (each cycle is 21 days) | Mean change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of cancer patients. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. |
| EORTC QLQ - Hepatocellular Carcinoma 18 Questions (HCC18): Index Scores | Baseline to Cycle 6 Day 1 and Cycle 12 Day 1 (each cycle is 21 days) | Mean change from baseline in EORTC QLQ HCC18 Index Scores. The EORTC QLQ HCC18 is a specific questionnaire module that assesses quality of life of cancer patients related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. |
| Number of Participants With Adverse Events | From first dose up to 30 days after the last dose of study drug; up to approximately 4 years and 3 months | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, physical exams, electrocardiogram results and vital signs |
| Disease Control Rate (DCR) Assessed by IRC | From date of first dose to end of study (up to approximately 4 years and 3 months) | DCR is defined as the percentage of participants whose best overall response is CR, PR, or stable disease (SD) as assessed by the IRC using RECIST v1.1 |
Countries
China, France, Germany, Italy, Poland, Spain, Taiwan, United Kingdom
Participant flow
Recruitment details
This study was conducted at 73 study centers in Mainland China, Taiwan, Italy, Germany, France, Spain, Poland, and the United Kingdom.
Participants by arm
| Arm | Count |
|---|---|
| Tislelizumab Tislelizumab 200 mg administered intravenously once every 3 weeks until unacceptable toxicity, withdrawal of consent, or the time point at which the participant was no longer benefiting from therapy, as assessed by the investigator, whichever occurred first | 249 |
| Total | 249 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 180 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Sponsor Decision | 61 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Tislelizumab |
|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 12.54 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score 0 = Fully Active | 129 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score 1 = Restricted Activity | 120 Participants |
| Race/Ethnicity, Customized Asian | 123 Participants |
| Race/Ethnicity, Customized Not Reported | 78 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 47 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 217 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 180 / 249 |
| other Total, other adverse events | 226 / 249 |
| serious Total, serious adverse events | 94 / 249 |
Outcome results
Primary
Objective Response Rate (ORR) Assessed by Independent Review Committee (IRC)
ORR is defined as the percentage of participants with complete response (CR) and partial response (PR) as the best overall response, as determined by an IRC using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions.
Time frame: From date of first dose to primary analysis data cut-off date of 30-June-2021 (up to approximately 3 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | Objective Response Rate (ORR) Assessed by Independent Review Committee (IRC) | 12.9 Percentage of participants |
Comparison: Tislelizumab compared with historical ORR rate of 7%p-value: 0.0001Binomial exact test
Secondary
CBR Assessed by Investigator
CBR is defined as the percentage of participants who have CR, PR, or SD of ≥ 24 weeks in duration as assessed by the investigator using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | CBR Assessed by Investigator | 30.9 Percentage of participants |
Secondary
Clinical Benefit Rate (CBR) Assessed by IRC
CBR is defined as the percentage of participants who have CR, PR, or SD of ≥ 24 weeks in duration as assessed by the IRC using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | Clinical Benefit Rate (CBR) Assessed by IRC | 22.5 Percentage of participants |
Secondary
DCR Assessed by Investigator
DCR is defined as the percentage of participants whose best overall response is CR, PR, or stable disease (SD) as assessed by the investigator using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | DCR Assessed by Investigator | 59.0 Percentage of participants |
Secondary
Disease Control Rate (DCR) Assessed by IRC
DCR is defined as the percentage of participants whose best overall response is CR, PR, or stable disease (SD) as assessed by the IRC using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | Disease Control Rate (DCR) Assessed by IRC | 53.0 Percentage of participants |
Secondary
DOR Assessed by Investigator
DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the investigator using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | DOR Assessed by Investigator | 21.4 Months |
Secondary
DOR Event-Free Rate Assessed by Investigator
DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the investigator using RECIST v1.1. The Kaplan-Meier method was used to estimate the percentage of participants who were event-free for progression or death at 12 and 24 months with 95% confidence intervals estimated using Greenwood's formula.
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months); Months 12 and 24 reported
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tislelizumab | DOR Event-Free Rate Assessed by Investigator | 12 Months | 68.1 Percentage of participants |
| Tislelizumab | DOR Event-Free Rate Assessed by Investigator | 24 Months | 47.4 Percentage of participants |
Secondary
DOR Event-Free Rate Assessed by IRC
DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the IRC using RECIST v1.1. The Kaplan-Meier method was used to estimate the percentage of participants who were event-free for progression or death at 12 and 24 months with 95% confidence intervals estimated using Greenwood's formula.
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months); Months 12 and 24 reported
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tislelizumab | DOR Event-Free Rate Assessed by IRC | 12 Months | 76.9 Percentage of participants |
| Tislelizumab | DOR Event-Free Rate Assessed by IRC | 24 Months | 65.9 Percentage of participants |
Secondary
Duration of Response (DOR) Assessed by IRC
DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first, as assessed by the IRC using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | Duration of Response (DOR) Assessed by IRC | NA Months |
Secondary
EORTC QLQ - Hepatocellular Carcinoma 18 Questions (HCC18): Index Scores
Mean change from baseline in EORTC QLQ HCC18 Index Scores. The EORTC QLQ HCC18 is a specific questionnaire module that assesses quality of life of cancer patients related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes.
Time frame: Baseline to Cycle 6 Day 1 and Cycle 12 Day 1 (each cycle is 21 days)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug; Overall number of participants analyzed refers to number of participants evaluable for this outcome measure and Number analyzed refers to participants evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tislelizumab | EORTC QLQ - Hepatocellular Carcinoma 18 Questions (HCC18): Index Scores | Baseline | 13.6 Score on a scale | Standard Deviation 11.33 |
| Tislelizumab | EORTC QLQ - Hepatocellular Carcinoma 18 Questions (HCC18): Index Scores | Change at Cycle 6 | 1.4 Score on a scale | Standard Deviation 11.77 |
| Tislelizumab | EORTC QLQ - Hepatocellular Carcinoma 18 Questions (HCC18): Index Scores | Change at Cycle 12 | 0.1 Score on a scale | Standard Deviation 8.27 |
Secondary
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status
Mean change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of cancer patients. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes.
Time frame: Baseline to Cycle 6 Day 1 and Cycle 12 Day 1 (each cycle is 21 days)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug; Overall number of participants analyzed refers to number of participants evaluable for this outcome measure and Number analyzed refers to participants evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tislelizumab | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | Baseline | 71.8 Score on a scale | Standard Deviation 19.37 |
| Tislelizumab | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | Change at Cycle 6 | -0.1 Score on a scale | Standard Deviation 17.5 |
| Tislelizumab | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | Change at Cycle 12 | 1.1 Score on a scale | Standard Deviation 18.63 |
Secondary
European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) Visual Analogue Score (VAS)
Mean change from baseline in EQ-5D-5L VAS. The EQ-5D-5L measures health outcomes using a VAS to record a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes.
Time frame: Baseline to Cycle 6 Day 1 and Cycle 12 Day 1 (each cycle is 21 days)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug; Overall number of participants analyzed refers to number of participants evaluable for this outcome measure and Number analyzed refers to participants evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tislelizumab | European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) Visual Analogue Score (VAS) | Baseline | 75.2 Score on a scale | Standard Deviation 18.36 |
| Tislelizumab | European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) Visual Analogue Score (VAS) | Change at Cycle 6 | 2.4 Score on a scale | Standard Deviation 12.57 |
| Tislelizumab | European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) Visual Analogue Score (VAS) | Change at Cycle 12 | 4.7 Score on a scale | Standard Deviation 13.85 |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, physical exams, electrocardiogram results and vital signs
Time frame: From first dose up to 30 days after the last dose of study drug; up to approximately 4 years and 3 months
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tislelizumab | Number of Participants With Adverse Events | Participants with a serious TEAE | 94 Participants |
| Tislelizumab | Number of Participants With Adverse Events | Participants with at least 1 TEAE | 236 Participants |
Secondary
ORR Assessed by Investigator
ORR is defined as the percentage of participants with CR and PR as the best overall response, as determined by investigator assessment using RECIST v1.1. CR is defined as disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions.
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tislelizumab | ORR Assessed by Investigator | 14.5 Percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from first study drug administration to the date of death due to any cause
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | Overall Survival (OS) | 13.2 Months |
Secondary
PFS Assessed by Investigator
PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by the investigator using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | PFS Assessed by Investigator | 2.8 Months |
Secondary
Progression-free Survival (PFS) Assessed by IRC
PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by the IRC using RECIST v1.1
Time frame: From date of first dose to end of study (up to approximately 4 years and 3 months)
Population: Safety analysis set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tislelizumab | Progression-free Survival (PFS) Assessed by IRC | 2.7 Months |