Carcinoma, Hepatocellular
Conditions
Brief summary
This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have received no prior systemic treatment.
Detailed description
The participants will be randomized in a 2:1 ratio to one of the two treatment arms: Arm A (experimental arm): Atezolizumab +bevacizumab; Arm B (control arm): Sorafenib
Interventions
DRUGAtezolizumab
Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21 day cycle
DRUGBevacizumab
Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21 day cycle
DRUGSorafenib
Sorafenib will be administered by mouth, 400 mg twice per day, on days 1-21 of each 21-day cycle
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Locally advanced or metastatic and/or unresectable Hepatocellular Carcinoma (HCC) * No prior systemic therapy for HCC. Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity included in the label is allowed, provided that these medications are discontinued prior to randomization. * At least one measurable untreated lesion * ECOG Performance Status of 0 or 1 * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent * For men: agreement to remain abstinent * Child-Pugh class A
Exclusion criteria
* History of leptomeningeal disease * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan * Known active tuberculosis * History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last dose of sorafenib * Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC * Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding * A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment. * Moderate or severe ascites * History of hepatic encephalopathy * Co-infection of HBV and HCV * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases * Uncontrolled tumor-related pain * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Uncontrolled or symptomatic hypercalcemia * Treatment with systemic immunostimulatory agents * Inadequately controlled arterial hypertension * Prior history of hypertensive crisis or hypertensive encephalopathy * Evidence of bleeding diathesis or significant coagulopathy * History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration * Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture * Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses * Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure * Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in the Global Population | From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months) | OS was defined as the time from randomization to death from any cause. |
| Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| Overall Survival (OS) in the China Population | From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months) | OS was defined as the time from randomization to death from any cause. |
| PFS-IRF Per RECIST v1.1 in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. |
| Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. |
| PFS-IRF Per HCC mRECIST in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| TTP-IRF Per HCC mRECIST in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| Overall Survival by Baseline AFP in the Global Population | From randomization to death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | OS was defined as the time from randomization to death from any cause. Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed. |
| PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed. |
| ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR |
| PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed. |
| Time to Deterioration (TTD) in the Global Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | TTD was defined as the time from randomization to the first deterioration (decrease from baseline of \>/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks. |
| Number of Participants With Adverse Events (AEs) in the Global Population | Up to end of study (up to approximately 56 months) | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population | Post-dose on Day 1 of Cycle 1 (cycle length = 21 days) | — |
| Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days) | — |
| Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR |
| Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR |
| Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR |
| Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. |
| Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. |
| Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. |
| Time to Deterioration (TTD) in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | TTD was defined as the time from randomization to the first deterioration (decrease from baseline of \>/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks. |
| PFS-IRF Per HCC mRECIST in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| TTP-IRF Per HCC mRECIST in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population | Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months) | Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). |
| Number of Participants With Adverse Events (AEs) in the China Population | Up to end of study (up to approximately 56 months) | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population | Post-dose on Day 1 of Cycle 1 (cycle length = 21 days) | — |
| Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days) | — |
| Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population | Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 18 months) | — |
| Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population | Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 30 months) | — |
| Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR |
| ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR |
| Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population | Randomization up to CCOD of 29Aug2019 (up to approximately 18 months) | DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. |
Countries
Australia, Canada, China, Czechia, France, Germany, Hong Kong, Italy, Japan, Poland, Russia, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 117 sites in 17 countries: Australia, Canada, China, Czech Republic, Germany, Spain, France, United Kingdom, Hong Kong, Italy, Japan, Republic of Korea, Poland, Russian Federation, Singapore, Taiwan, United States.
Pre-assignment details
The total study population included 558 participants. The Global population included 501 participants. An additional 57 participants enrolled during the China Extension. The total China population included 137 Chinese participants from the Global population plus 57 participants from the China extension. 137 participants were part of the Global as well as China populations. Separate analyses were performed for the Global population and the China population in the study.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib - All All participants either in the Global or China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | 183 |
| Atezolizumab + Bevacizumab - All All participants either in the Global or China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | 375 |
| Total | 558 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| China Extension Period | Death | 0 | 0 | 46 | 88 |
| China Extension Period | Lost to Follow-up | 0 | 0 | 2 | 3 |
| China Extension Period | Study Ended by Sponsor | 0 | 0 | 5 | 36 |
| China Extension Period | Withdrawal by Subject | 0 | 0 | 8 | 6 |
| Global Period | Death | 115 | 228 | 0 | 0 |
| Global Period | Lost to Follow-up | 3 | 6 | 0 | 0 |
| Global Period | Physician Decision | 1 | 0 | 0 | 0 |
| Global Period | Reason Unspecified | 0 | 1 | 0 | 0 |
| Global Period | Study Ended by Sponsor | 26 | 80 | 0 | 0 |
| Global Period | Withdrawal by Subject | 20 | 21 | 0 | 0 |
Baseline characteristics
| Characteristic | Sorafenib - All | Atezolizumab + Bevacizumab - All | Total |
|---|---|---|---|
| Age, Continuous China | 57.5 years STANDARD_DEVIATION 12.7 | 55.3 years STANDARD_DEVIATION 12 | 56.0 years STANDARD_DEVIATION 12.3 |
| Age, Continuous Global | 64.4 years STANDARD_DEVIATION 10.9 | 62.9 years STANDARD_DEVIATION 11.9 | 63.4 years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) China Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) China Not Hispanic or Latino | 61 Participants | 133 Participants | 194 Participants |
| Ethnicity (NIH/OMB) China Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Global Hispanic or Latino | 4 Participants | 9 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Global Not Hispanic or Latino | 149 Participants | 306 Participants | 455 Participants |
| Ethnicity (NIH/OMB) Global Unknown or Not Reported | 12 Participants | 21 Participants | 33 Participants |
| Race (NIH/OMB) China American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China Asian | 61 Participants | 133 Participants | 194 Participants |
| Race (NIH/OMB) China Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China White | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Global American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Global Asian | 96 Participants | 188 Participants | 284 Participants |
| Race (NIH/OMB) Global Black or African American | 4 Participants | 6 Participants | 10 Participants |
| Race (NIH/OMB) Global More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Global Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Global Unknown or Not Reported | 12 Participants | 19 Participants | 31 Participants |
| Race (NIH/OMB) Global White | 52 Participants | 123 Participants | 175 Participants |
| Sex: Female, Male China Female | 12 Participants | 17 Participants | 29 Participants |
| Sex: Female, Male China Male | 49 Participants | 116 Participants | 165 Participants |
| Sex: Female, Male Global Female | 28 Participants | 59 Participants | 87 Participants |
| Sex: Female, Male Global Male | 137 Participants | 277 Participants | 414 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 | 115 / 165 | 228 / 336 | 46 / 61 | 88 / 133 |
| other Total, other adverse events | 147 / 156 | 311 / 329 | 55 / 58 | 129 / 132 |
| serious Total, serious adverse events | 51 / 156 | 171 / 329 | 12 / 58 | 54 / 132 |
Outcome results
Primary
Overall Survival (OS) in the China Population
OS was defined as the time from randomization to death from any cause.
Time frame: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib - Global | Overall Survival (OS) in the China Population | At CCOD 18 months | 11.37 months |
| Sorafenib - Global | Overall Survival (OS) in the China Population | At CCOD 30 months | 11.37 months |
| Atezolizumab + Bevacizumab - Global | Overall Survival (OS) in the China Population | At CCOD 18 months | NA months |
| Atezolizumab + Bevacizumab - Global | Overall Survival (OS) in the China Population | At CCOD 30 months | 24.05 months |
Comparison: At CCOD 18 months; Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.002695% CI: [0.25, 0.76]Log Rank
Comparison: At CCOD 30 months; Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.001995% CI: [0.35, 0.8]Log Rank
Primary
Overall Survival (OS) in the Global Population
OS was defined as the time from randomization to death from any cause.
Time frame: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib - Global | Overall Survival (OS) in the Global Population | At CCOD 30 months | 13.40 months |
| Sorafenib - Global | Overall Survival (OS) in the Global Population | At CCOD 18 months | 13.24 months |
| Atezolizumab + Bevacizumab - Global | Overall Survival (OS) in the Global Population | At CCOD 18 months | NA months |
| Atezolizumab + Bevacizumab - Global | Overall Survival (OS) in the Global Population | At CCOD 30 months | 19.22 months |
Comparison: At CCOD 18 months; Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline alpha-fetoprotein (AFP: \<400 vs. \>/= 400 ng/mL).p-value: 0.000695% CI: [0.42, 0.79]Log Rank
Comparison: At CCOD 30 months; Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline alpha-fetoprotein (AFP: \<400 vs. \>/= 400 ng/mL).p-value: 0.000995% CI: [0.52, 0.85]Log Rank
Primary
PFS-IRF Per RECIST v1.1 in the China Population
PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | PFS-IRF Per RECIST v1.1 in the China Population | 3.19 months |
| Atezolizumab + Bevacizumab - Global | PFS-IRF Per RECIST v1.1 in the China Population | 5.72 months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.011795% CI: [0.4, 0.9]Log Rank
Primary
Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population
PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population | 4.27 months |
| Atezolizumab + Bevacizumab - Global | Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population | 6.83 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [0.47, 0.76]Log Rank
Secondary
Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population
DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: The analysis population included China participants with a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population | 5.55 months |
| Atezolizumab + Bevacizumab - Global | Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population | NA months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.347795% CI: [0.03, 3.69]Log Rank
Secondary
Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population
DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: The analysis population included Global participants with a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population | NA months |
| Atezolizumab + Bevacizumab - Global | Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population | 13.08 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.418795% CI: [0.16, 2.15]Log Rank
Secondary
Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population
DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: The analysis population included China participants with a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population | 4.86 months |
| Atezolizumab + Bevacizumab - Global | Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population | NA months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.0195% CI: [0.01, 0.91]Log Rank
Secondary
Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population
DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: The analysis population included Global participants with a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population | 6.28 months |
| Atezolizumab + Bevacizumab - Global | Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population | NA months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.004895% CI: [0.12, 0.73]Log Rank
Secondary
Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population
DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: The analysis population included China participants with a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population | NA months |
| Atezolizumab + Bevacizumab - Global | Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population | NA months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.458195% CI: [0.02, 5.85]Log Rank
Secondary
Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population
DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: The analysis population included Global participants with a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population | 6.28 months |
| Atezolizumab + Bevacizumab - Global | Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population | NA months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.005195% CI: [0.08, 0.7]Log Rank
Secondary
Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population
Time frame: Post-dose on Day 1 of Cycle 1 (cycle length = 21 days)
Population: The Global pharmacokinetic (PK)-evaluable population was defined as all participants in the Global population who received any dose of study treatment and who had at least one post-baseline PK sample available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib - Global | Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population | 398 micrograms/milliliter (mcg/mL) | Standard Deviation 132 |
Secondary
Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population
Time frame: Post-dose on Day 1 of Cycle 1 (cycle length = 21 days)
Population: The China PK-evaluable population was defined as all participants in the China population who received any dose of study treatment and who had at least one post-baseline PK sample available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib - Global | Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population | 456 mcg/mL | Standard Deviation 153 |
Secondary
Number of Participants With Adverse Events (AEs) in the China Population
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Up to end of study (up to approximately 56 months)
Population: China safety population included all randomized China participants who received any amount of study drug with participants grouped according to the treatment the participant actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sorafenib - Global | Number of Participants With Adverse Events (AEs) in the China Population | 56 Participants |
| Atezolizumab + Bevacizumab - Global | Number of Participants With Adverse Events (AEs) in the China Population | 131 Participants |
Secondary
Number of Participants With Adverse Events (AEs) in the Global Population
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Up to end of study (up to approximately 56 months)
Population: Global safety population included all randomized Global participants who received any amount of study drug with participants grouped according to the treatment the participant actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sorafenib - Global | Number of Participants With Adverse Events (AEs) in the Global Population | 154 Participants |
| Atezolizumab + Bevacizumab - Global | Number of Participants With Adverse Events (AEs) in the Global Population | 322 Participants |
Secondary
Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population
ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population with measurable disease at baseline consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population | 8.5 percentage of participants |
| Atezolizumab + Bevacizumab - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population | 29.7 percentage of participants |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.001395% CI: [1.72, 12.87]Cochran-Mantel-Haenszel
Secondary
Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population
ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population with measurable disease at baseline consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population | 13.3 percentage of participants |
| Atezolizumab + Bevacizumab - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population | 33.2 percentage of participants |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [2.02, 5.71]Cochran-Mantel-Haenszel
Secondary
Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population
ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population with measurable disease at baseline consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population | 6.7 percentage of participants |
| Atezolizumab + Bevacizumab - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population | 24.6 percentage of participants |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.003695% CI: [1.53, 13.86]Cochran-Mantel-Haenszel
Secondary
Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population
ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population with measurable disease at baseline consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population | 11.9 percentage of participants |
| Atezolizumab + Bevacizumab - Global | Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population | 27.3 percentage of participants |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [1.68, 5.01]Cochran-Mantel-Haenszel
Secondary
ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population
ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population with measurable disease at baseline consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib - Global | ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population | 4.9 percentage of participants |
| Atezolizumab + Bevacizumab - Global | ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population | 21.1 percentage of participants |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.005295% CI: [1.47, 17.39]Cochran-Mantel-Haenszel
Secondary
ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population
ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR
Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population with measurable disease at baseline consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib - Global | ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population | 5.5 percentage of participants |
| Atezolizumab + Bevacizumab - Global | ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population | 25.6 percentage of participants |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [2.99, 12.66]Cochran-Mantel-Haenszel
Secondary
Overall Survival by Baseline AFP in the Global Population
OS was defined as the time from randomization to death from any cause. Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed.
Time frame: From randomization to death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Sorafenib - Global | Overall Survival by Baseline AFP in the Global Population | AFP <400 ng/mL | 13.93 months |
| Sorafenib - Global | Overall Survival by Baseline AFP in the Global Population | AFP >/=400 ng/mL | 9.10 months |
| Atezolizumab + Bevacizumab - Global | Overall Survival by Baseline AFP in the Global Population | AFP <400 ng/mL | NA months |
| Atezolizumab + Bevacizumab - Global | Overall Survival by Baseline AFP in the Global Population | AFP >/=400 ng/mL | 12.78 months |
Comparison: AFP \<400 ng/mL and stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).p-value: 0.001995% CI: [0.32, 0.78]Log Rank
Comparison: AFP \>/= 400 ng/mL and stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).p-value: 0.087995% CI: [0.42, 1.06]Log Rank
Secondary
Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population
Time frame: Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 18 months)
Population: The China ADA-evaluable population was defined as all participants in the China population who received any dose of atezolizumab and who had at least one post-baseline ADA assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib - Global | Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population | Baseline | 1.1 percentage of participants |
| Sorafenib - Global | Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population | Post-baseline | 20.2 percentage of participants |
Secondary
Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population
Time frame: Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 30 months)
Population: The Global ADA-evaluable population was defined as all participants in the Global population who received any dose of atezolizumab and who had at least one post-baseline ADA assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib - Global | Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population | Baseline | 2.2 percentage of participants |
| Sorafenib - Global | Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population | Post-baseline | 29.6 percentage of participants |
Secondary
PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population
PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population | 2.83 months |
| Atezolizumab + Bevacizumab - Global | PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population | 5.55 months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.000295% CI: [0.33, 0.71]Log Rank
Secondary
PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population
PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population | 2.89 months |
| Atezolizumab + Bevacizumab - Global | PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population | 7.06 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [0.36, 0.57]Log Rank
Secondary
PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population
PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed.
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib - Global | PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population | AFP <400 ng/mL | 3.98 months |
| Sorafenib - Global | PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population | AFP >/=400 ng/mL | 2.79 months |
| Atezolizumab + Bevacizumab - Global | PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population | AFP <400 ng/mL | 8.41 months |
| Atezolizumab + Bevacizumab - Global | PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population | AFP >/=400 ng/mL | 5.42 months |
Comparison: AFP \<400 ng/mL and stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).p-value: <0.000195% CI: [0.31, 0.57]Log Rank
Comparison: AFP \>/=400 ng/mL and stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).p-value: 0.000295% CI: [0.35, 0.73]Log Rank
Secondary
PFS-IRF Per HCC mRECIST in the China Population
PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | PFS-IRF Per HCC mRECIST in the China Population | 3.19 months |
| Atezolizumab + Bevacizumab - Global | PFS-IRF Per HCC mRECIST in the China Population | 5.72 months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.010395% CI: [0.4, 0.89]Log Rank
Secondary
PFS-IRF Per HCC mRECIST in the Global Population
PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | PFS-IRF Per HCC mRECIST in the Global Population | 4.24 months |
| Atezolizumab + Bevacizumab - Global | PFS-IRF Per HCC mRECIST in the Global Population | 6.83 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [0.46, 0.74]Log Rank
Secondary
PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population
PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed.
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib - Global | PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population | AFP <400 ng/mL | 4.40 months |
| Sorafenib - Global | PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population | AFP >/=400 ng/mL | 4.14 months |
| Atezolizumab + Bevacizumab - Global | PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population | AFP <400 ng/mL | 8.28 months |
| Atezolizumab + Bevacizumab - Global | PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population | AFP >/=400 ng/mL | 5.19 months |
Comparison: AFP\<400 ng/mL and stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).p-value: <0.000195% CI: [0.37, 0.68]Log Rank
Comparison: AFP \>/=400 ng/mL and stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).p-value: 0.215995% CI: [0.53, 1.15]Log Rank
Secondary
Time to Deterioration (TTD) in the China Population
TTD was defined as the time from randomization to the first deterioration (decrease from baseline of \>/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks.
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib - Global | Time to Deterioration (TTD) in the China Population | Physical Functioning | 5.62 months |
| Sorafenib - Global | Time to Deterioration (TTD) in the China Population | Role Functioning | NA months |
| Sorafenib - Global | Time to Deterioration (TTD) in the China Population | GHS/QoL | 3.58 months |
| Atezolizumab + Bevacizumab - Global | Time to Deterioration (TTD) in the China Population | Physical Functioning | 13.14 months |
| Atezolizumab + Bevacizumab - Global | Time to Deterioration (TTD) in the China Population | Role Functioning | NA months |
| Atezolizumab + Bevacizumab - Global | Time to Deterioration (TTD) in the China Population | GHS/QoL | 9.76 months |
Comparison: Physical Functioning: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.003595% CI: [0.26, 0.78]Log Rank
Comparison: Role Functioning: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.221495% CI: [0.42, 1.23]Log Rank
Comparison: GHS/QoL: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.013595% CI: [0.32, 0.88]Log Rank
Secondary
Time to Deterioration (TTD) in the Global Population
TTD was defined as the time from randomization to the first deterioration (decrease from baseline of \>/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks.
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib - Global | Time to Deterioration (TTD) in the Global Population | Physical Functioning | 4.86 months |
| Sorafenib - Global | Time to Deterioration (TTD) in the Global Population | Role Functioning | 3.58 months |
| Sorafenib - Global | Time to Deterioration (TTD) in the Global Population | GHS/QoL | 3.58 months |
| Atezolizumab + Bevacizumab - Global | Time to Deterioration (TTD) in the Global Population | Physical Functioning | 13.14 months |
| Atezolizumab + Bevacizumab - Global | Time to Deterioration (TTD) in the Global Population | Role Functioning | 9.13 months |
| Atezolizumab + Bevacizumab - Global | Time to Deterioration (TTD) in the Global Population | GHS/QoL | 11.24 months |
Comparison: Physical Functioning: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [0.39, 0.73]Log Rank
Comparison: Role Functioning: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.001995% CI: [0.46, 0.84]Log Rank
Comparison: GHS/QoL: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.002895% CI: [0.46, 0.85]Log Rank
Secondary
Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population
Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population | 4.14 months |
| Atezolizumab + Bevacizumab - Global | Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population | 7.00 months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.092795% CI: [0.43, 1.07]Log Rank
Secondary
Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population
Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population | 5.59 months |
| Atezolizumab + Bevacizumab - Global | Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population | 8.57 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.010595% CI: [0.53, 0.92]Log Rank
Secondary
Trough Serum Concentration (Cmin) of Atezolizumab in the China Population
Time frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days)
Population: The China PK-evaluable population was defined as all participants in the China population who received any dose of study treatment and who had at least one post-baseline PK sample available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose Cycle 2, Day 1 | 92.6 mcg/mL | Standard Deviation 65.7 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose Cycle 3, Day 1 | 105 mcg/mL | Standard Deviation 36.8 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose Cycle 4, Day 1 | 143 mcg/mL | Standard Deviation 61.4 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose Cycle 8, Day 1 | 177 mcg/mL | Standard Deviation 61.9 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose Cycle 12, Day 1 | 201 mcg/mL | Standard Deviation 97.6 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the China Population | Pre-dose Cycle 16, Day 1 | 208 mcg/mL | Standard Deviation 79.4 |
Secondary
Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population
Time frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days)
Population: The Global pharmacokinetic (PK)-evaluable population was defined as all participants in the Global population who received any dose of study treatment and who had at least one post-baseline PK sample available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose Cycle 2, Day 1 | 79.2 mcg/mL | Standard Deviation 50.2 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose Cycle 3, Day 1 | 101 mcg/mL | Standard Deviation 55.4 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose Cycle 4, Day 1 | 131 mcg/mL | Standard Deviation 63.7 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose Cycle 8, Day 1 | 145 mcg/mL | Standard Deviation 61.7 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose Cycle 12, Day 1 | 168 mcg/mL | Standard Deviation 82.9 |
| Sorafenib - Global | Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population | Pre-dose Cycle 16, Day 1 | 167 mcg/mL | Standard Deviation 65 |
Secondary
TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population
Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population | 2.83 months |
| Atezolizumab + Bevacizumab - Global | TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population | 6.83 months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.000495% CI: [0.33, 0.74]Log Rank
Secondary
TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population
Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population | 3.98 months |
| Atezolizumab + Bevacizumab - Global | TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population | 8.54 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: <0.000195% CI: [0.35, 0.57]Log Rank
Secondary
TTP-IRF Per HCC mRECIST in the China Population
Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | TTP-IRF Per HCC mRECIST in the China Population | 4.14 months |
| Atezolizumab + Bevacizumab - Global | TTP-IRF Per HCC mRECIST in the China Population | 7.00 months |
Comparison: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.086195% CI: [0.43, 1.06]Log Rank
Secondary
TTP-IRF Per HCC mRECIST in the Global Population
Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
Population: Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib - Global | TTP-IRF Per HCC mRECIST in the Global Population | 5.55 months |
| Atezolizumab + Bevacizumab - Global | TTP-IRF Per HCC mRECIST in the Global Population | 8.28 months |
Comparison: Stratified by geographic region (Asia \[excluding Japan\] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (\<400 vs. \>/= 400 ng/mL).p-value: 0.006395% CI: [0.52, 0.9]Log Rank