A Study of Tislelizumab Versus Sorafenib in Participants With Unresectable Hepatocellular Carcinoma (HCC)

Phase 3

Completed

Conditions: Hepatocellular Carcinoma (HCC)

Interventions: Drug: Tislelizumab
Drug: Sorafenib

Registration Number: NCT03412773

Lead Sponsor: BeiGene

Brief Summary: This Phase 3 study was a global, multicenter trial that randomly assigned participants to either tislelizumab or sorafenib as a first-line treatment for adults with advanced liver cancer (hepatocellular carcinoma) that could not be surgically removed. Before enrolling Japanese participants in the main Phase 3 study, a preliminary assessment of safety and tolerability (the Safety Run-In Sub-study) was conducted in Japan.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 684

Inclusion Criteria

Histologically confirmed diagnosis of HCC
Barcelona Clinic Liver Cancer (BCLC) Stage B or C disease not amenable to or progressing after loco-regional therapy and not amenable to a curative treatment approach
No prior systemic therapy for HCC (with the exception of HCC participants enrolled in the safety run-in substudy [Japan only])
Measurable disease
Child-Pugh score A
Easter Cooperative Oncology Group (ECOG) Performance Status ≤ 1
Adequate organ function

Main Study Key

Exclusion Criteria

Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC histology
Tumor thrombus involving main trunk of portal vein or inferior vena cava
Loco-regional therapy to the liver within 28 days before randomization
Clinical evidence of portal hypertension with bleeding esophageal or gastric varices at Screening, or within 6 months before randomization
Bleeding or thrombotic disorder or any prescribed anticoagulant requiring therapeutic international normalized ratio monitoring (eg, warfarin or similar agents) at Screening, or within 6 months before randomization/enrollment
Presence at Screening of active immune deficiency or autoimmune disease and/or prior history of any immune deficiency or autoimmune disease that may relapse
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 randomization
History of interstitial lung disease or non-infectious pneumonitis, unless induced by radiation therapy
QT interval corrected for heart rate (QTc) (corrected by Fridericia's method) > 450 msec at Screening

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Safety Run-In Sub-study	Tislelizumab	Japanese participants received 200 mg intravenous tislelizumab every 3 weeks to assess preliminary safety and tolerability.
Arm A: Tislelizumab	Tislelizumab	Participants received 200 mg of intravenous tislelizumab every 3 weeks until intolerable toxicity, withdrawal of consent, or the investigator determined no further benefit from the therapy.
Arm B: Sorafenib	Sorafenib	Participants received 400 mg of oral sorafenib twice daily until intolerable toxicity, consent withdrawal, or the investigator deemed no further benefit.

Primary Outcome Measures

Name	Time	Method
Safety Run-in Sub-study: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From the first dose to 30 days after the last dose, new anticancer therapy, or the analysis cutoff of December 14th, 2023 (a maximum of 64 months)	An adverse event (AE) is any unfavorable or unintended sign (e.g., abnormal lab result), symptom, or disease temporally associated with study drug use, regardless of causality. A serious adverse event (SAE) is defined as any adverse event that: * Resulted in death * Was life-threatening * Required or prolonged hospitalization * Caused disability/incapacity * Lead to a congenital anomaly/birth defect * Was deemed medically significant by the investigator (e.g., required intervention to prevent severe outcomes).
Safety Run-in Sub-study: Serum Concentration of Tislelizumab	Cycle 1 and Cycle 5 at end of infusion, 24 hand 72 hours post-dose, and 8 days and 15 days post-dose (each cycle was 3 weeks).	Serum concentration of tislelizumab was a pre-specified primary endpoint for the sub-study only.
Main Study: Overall Survival (OS)	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the time from the date of randomization to the date of death due to any cause. Median OS was estimated using Kaplan-Meier methodology. Overall survival was a pre-specified primary endpoint for the main study only.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) as Assessed by Blinded Independent Review Committee (BIRC)	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the percentage of participants who had partial response or complete response as determined by Blinded Independent Review Committee (BIRC) per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in all randomized participants with measurable disease at baseline. ORR was not assessed by the BIRC for participants in the sub-study, and this was not a pre-specified sub-study endpoint.
Overall Response Rate (ORR) as Assessed by the Investigator	Through the study completion data cut-off date of December 14th, 2023 (up to approximately 65 months)	Defined as the percentage of participants who had partial response or complete response as determined by the investigator per RECIST v1.1 in all randomized participants with measurable disease at baseline.
Progression Free Survival (PFS) as Assessed by BIRC	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the BIRC per RECIST v1.1. Kaplan-Meier methodology was used to estimate the median PFS. PFS was not assessed by the BIRC for participants in the sub-study, and this was not a pre-specified sub-study endpoint.
Progression Free Survival (PFS) Assessed by the Investigator	Through the study completion data cut-off date of December 14th, 2023 (up to approximately 65 months)	Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the investigator per RECIST v1.1. Kaplan-Meier methodology was used to estimate the median PFS.
Duration of Response (DOR) as Assessed by BIRC	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the time from the first occurrence of a documented objective response until the first documentation of progression or death from any cause, whichever occurred first, as determined by the BIRC per RECIST v1.1. Median DOR was estimated using Kaplan-Meier methodology. DOR was not assessed by the BIRC for participants in the sub-study, and this was not a pre-specified sub-study endpoint.
Duration of Response (DOR) Assessed by the Investigator	Through the study completion data cut-off date of December 14th, 2023 (up to approximately 65 months)	Defined as the time from the first occurrence of a documented objective response until the first documentation of progression or death from any cause, whichever occurred first, as assessed by the investigator per RECIST v1.1. Median DOR was estimated using Kaplan-Meier methodology.
Time to Progression (TTP) Assessed by BIRC	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed by the BIRC per RECIST v1.1. Median TTP was estimated using Kaplan-Meier methodology. TTP was not assessed by the BIRC for participants in the sub-study, and this was not a pre-specified sub-study endpoint.
Time to Progression (TTP) as Assessed by the Investigator	Through the study completion data cut-off date of December 14th, 2023 (up to approximately 65 months)	Defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed by the investigator per RECIST v1.1. Median TTP was estimated using Kaplan-Meier methodology. TTP was not a pre-specified sub-study endpoint.
Safety Run-in Sub-study: Overall Survival	Up a to 64 months	Defined as the time from the date of randomization to the date of death due to any cause. Median OS was estimated using Kaplan-Meier methodology.
Disease Control Rate (DCR) as Assessed by BIRC	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the percentage of participants whose best overall response (BOR) was complete response, partial response, or stable disease as assessed by the BIRC per RECIST v1.1. DCR was not a pre-specified endpoint for participants in the sub-study.
Disease Control Rate (DCR) as Assessed by the Investigator	Through the study completion data cut-off date of December 14th, 2023 (up to approximately 65 months)	Defined as the percentage of participants whose best overall response (BOR) was complete response, partial response, or stable disease as assessed by the investigator per RECIST v1.1. DCR was not a pre-specified endpoint for participants in the sub-study.
Clinical Benefit Rate (CBR) as Assessed by BIRC	Through the primary analysis data cut-off date of July 11th, 2022 (up to approximately 55 months)	Defined as the percentage of participants whose best overall response (BOR) was complete response, partial response, or stable disease greater than or equal to 24 weeks in duration, as assessed by the BIRC per RECIST v1.1. CBR was not a pre-specified endpoint for participants in the sub-study.
Clinical Benefit Rate (CBR) as Assessed by the Investigator	Through the study completion data cut-off date of December 14th, 2023 (up to approximately 65 months)	Defined as the percentage of participants whose best overall response (BOR) is complete response, partial response, or stable disease greater than or equal to 24 weeks in duration, as assessed by the investigator per RECIST v1.1. CBR was not a pre-specified endpoint for participants in the sub-study.
Change From Baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Hepatocellular Carcinoma 18 Questions (EORTC QLQ HCC 18) Index Score at Cycle 4	Baseline to Cycle 4 (each cycle was 21 days)	The EORTC QLQ-HCC18 is a questionnaire specifically designed to assess health-related quality of life in participants with hepatocellular carcinoma. It includes six symptom scales measuring Fatigue (3 items), Jaundice (2 items), Body Image (2 items), Nutrition (5 items), Pain (2 items), Fever (2 items) and two single items measuring Sex Life and Abdominal Swelling. Participants respond on a scale from 1 = "Not at all" to 4 = "Very Much. Raw scores are transformed into a 0 to 100 scale using linear transformation. The HCC18 Index score is calculated from each of the 6 symptom scales and the 2 single items, and ranges from 0 to 100. Higher scores indicate greater symptom burden or worse quality of life. The EORTC QLQ-HCC18 was not assessed for participants in the sub-study.
Change From Baseline in the European EORTC QLQ HCC 18 Index Score at Cycle 6	Baseline to Cycle 6 (Each cycle was 21 days)	The EORTC QLQ-HCC18 is a questionnaire specifically designed to assess health-related quality of life in participants with hepatocellular carcinoma. It includes six symptom scales measuring Fatigue (3 items), Jaundice (2 items), Body Image (2 items), Nutrition (5 items), Pain (2 items), Fever (2 items) and two single items measuring Sex Life and Abdominal Swelling. Participants respond on a scale from 1 = "Not at all" to 4 = "Very Much. Raw scores are transformed into a 0 to 100 scale using linear transformation. The HCC18 Index score is calculated from each of the 6 symptom scales and the 2 single items, and ranges from 0 to 100. Higher scores indicate greater symptom burden or worse quality of life. The HEORTC QLQ-HCC18 was not assessed in participants in the sub-study.
Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Score at Cycle 4	Baseline to Cycle 4 (each cycle was 21 days)	The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of participants with cancer. 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. The EORTC QLQ-C30 was not assessed in participants in the sub-study.
Change From Baseline in the EQ-5D-5L VAS at Cycle 6	Baseline to Cycle 6 (each cycle was 21 days)	The EQ-5D-5L comprises a descriptive module and a visual analogue scale (VAS). The EQ-5D-5L VAS measures respondent's self-rated health status on a 0 to 100 scale, with 100 = 'the best health you can imagine' and 0 = 'the worst health you can imagine'. Higher scores on VAS indicate higher health status. The EQ-5D-5L VAS was not assessed in participants in the sub-study.
Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life Score at Cycle 6	Baseline to Cycle 6 (each cycle was 21 days)	The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of participants with cancer. 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. The EORTC QLQ-C30 was not assessed in participants in the sub-study.
Change From Baseline in the European Quality of Life 5 Dimensions, 5-level (EQ-5D-5L) Visual Analogue Scale (VAS) at Cycle 4	Baseline to Cycle 4 (each cycle was 21 days)	The EQ-5D-5L comprises a descriptive module and a Visual Analogue scale (VAS). The EQ-5D-5L VAS measures respondent's self-rated health status on a 0 to 100 scale, with 100 = 'the best health you can imagine' and 0 = 'the worst health you can imagine'. Higher scores on VAS indicate higher health status. The EQ-5D-5L VAS was not assessed in participants in the sub-study.
Main Study: Number of Participants With Treatment-emergent Adverse Events	From the first dose to 30 days after the last dose, new anticancer therapy, or the study completion analysis cutoff on December 14th, 2023 (a maximum of 61 months for participants in Arm A and 63 months for participants in Arm B).	An adverse event (AE) is any unfavorable or unintended sign (e.g., abnormal lab result), symptom, or disease temporally associated with study drug use, regardless of causality. A serious adverse event (SAE) is defined as any adverse event that: * Resulted in death * Was life-threatening * Required or prolonged hospitalization * Caused disability/incapacity * Lead to a congenital anomaly/birth defect * Was deemed medically significant by the investigator (e.g., required intervention to prevent severe outcomes).
Safety Run-in Sub-study: Number of Participants Who Developed Anti-tislelizumab Antibodies	From the first dose to 30 days after the last dose, new anticancer therapy, or the analysis cutoff of December 14th, 2023 (a maximum of 64 months)	Treatment-emergent anti-drug antibodies (ADA): participants who were ADA negative at baseline and ADA positive post-baseline. Treatment-boosted ADA: participants who were ADA positive at baseline that was boosted to a 4-fold or higher-level following drug administration. ADA assessments were not performed for participants enrolled in the main study.

Trial Locations

Locations (122): Providence Medical Foundation
🇺🇸
Fullerton, California, United States
UCLA Hematologyoncology
🇺🇸
Los Angeles, California, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Umdnj Njms
🇺🇸
Newark, New Jersey, United States
Rj Zuckerberg Cancer Center
🇺🇸
Lake Success, New York, United States
Xcancerdayton Physician Network
🇺🇸
Dayton, Ohio, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Ut Health San Antonio Mays Cancer Center
🇺🇸
San Antonio, Texas, United States
The First Affiliated Hospital of Anhui Medical University
🇨🇳
Hefei, Anhui, China
The Second Hospital of Anhui Medical University
🇨🇳
Hefei, Anhui, China
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Providence Medical Foundation
🇺🇸Fullerton, California, United States