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A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma (IMbrave150)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03434379
Recruitment Status : Completed
First Posted : February 15, 2018
Results First Posted : November 5, 2021
Last Update Posted : November 25, 2022
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Carcinoma, Hepatocellular
Interventions Drug: Atezolizumab
Drug: Bevacizumab
Drug: Sorafenib
Enrollment 558
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.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Period Title: Global Period
Started 165 336 0 0
Completed 0 0 0 0
Not Completed 165 336 0 0
Reason Not Completed
Lost to Follow-up             3             1             0             0
Death             99             179             0             0
Withdrawal by Subject             20             20             0             0
On Study             43             136             0             0
Period Title: China Extension Period
Started 0 0 61 [1] 133 [2]
Completed 0 0 0 0
Not Completed 0 0 61 133
Reason Not Completed
Lost to Follow-up             0             0             1             0
Death             0             0             38             61
Withdrawal by Subject             0             0             7             6
On Study             0             0             15             66
[1]
n=43 Chinese participants from the sorafenib Global population are included in the China population.
[2]
n=94 Chinese participants from the Atezolizumab + Bevacizumab Global population are included in the China population.
Arm/Group Title Sorafenib - All Atezolizumab + Bevacizumab - All Total
Hide Arm/Group Description All participants either in the Global or China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. 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. Total of all reporting groups
Overall Number of Baseline Participants 183 375 558
Hide Baseline Analysis Population Description
The intent-to-treat (ITT) population included 558 participants (All) with 501 in the Global population. An additional 57 participants enrolled in the China Extension. The China population included 137 Chinese participants from the Global population plus 57 participants from the China Extension. The Global population and China population were analyzed separately.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Global Number Analyzed 165 participants 336 participants 501 participants
64.4  (10.9) 62.9  (11.9) 63.4  (11.6)
China Number Analyzed 61 participants 133 participants 194 participants
57.5  (12.7) 55.3  (12.0) 56.0  (12.3)
[1]
Measure Analysis Population Description: The Global population included 501 participants. The China population included 57 participants enrolled during the China Extension plus 137 Chinese participants from the Global population.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Global Number Analyzed 165 participants 336 participants 501 participants
Female
28
  17.0%
59
  17.6%
87
  17.4%
Male
137
  83.0%
277
  82.4%
414
  82.6%
China Number Analyzed 61 participants 133 participants 194 participants
Female
12
  19.7%
17
  12.8%
29
  14.9%
Male
49
  80.3%
116
  87.2%
165
  85.1%
[1]
Measure Analysis Population Description: The Global population included 501 participants. The China population included 57 participants enrolled during the China Extension plus 137 Chinese participants from the Global population.
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Global Number Analyzed 165 participants 336 participants 501 participants
Hispanic or Latino
4
   2.4%
9
   2.7%
13
   2.6%
Not Hispanic or Latino
149
  90.3%
306
  91.1%
455
  90.8%
Unknown or Not Reported
12
   7.3%
21
   6.3%
33
   6.6%
China Number Analyzed 61 participants 133 participants 194 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
61
 100.0%
133
 100.0%
194
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Analysis Population Description: The Global population included 501 participants. The China population included 57 participants enrolled during the China Extension plus 137 Chinese participants from the Global population.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Global Number Analyzed 165 participants 336 participants 501 participants
American Indian or Alaska Native
1
   0.6%
0
   0.0%
1
   0.2%
Asian
96
  58.2%
188
  56.0%
284
  56.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
   2.4%
6
   1.8%
10
   2.0%
White
52
  31.5%
123
  36.6%
175
  34.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
12
   7.3%
19
   5.7%
31
   6.2%
China Number Analyzed 61 participants 133 participants 194 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
61
 100.0%
133
 100.0%
194
 100.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Analysis Population Description: The Global population included 501 participants. The China population included 57 participants enrolled during the China Extension plus 137 Chinese participants from the Global population.
1.Primary Outcome
Title Overall Survival (OS) in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
At CCOD 18 months
13.24 [1] 
(10.41 to NA)
NA [1] 
(NA to NA)
At CCOD 30 months
13.40
(11.37 to 16.85)
19.22
(17.02 to 23.66)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.42 to 0.79
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.52 to 0.85
Estimation Comments [Not Specified]
2.Primary Outcome
Title Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
4.27
(3.98 to 5.55)
6.83
(5.75 to 8.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.47 to 0.76
Estimation Comments [Not Specified]
3.Primary Outcome
Title Overall Survival (OS) in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
At CCOD 18 months
11.37 [1] 
(6.74 to NA)
NA [1] 
(13.50 to NA)
At CCOD 30 months
11.37
(6.74 to 16.07)
24.05 [1] 
(17.12 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments At CCOD 18 months; Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0026
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.25 to 0.76
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments At CCOD 30 months; Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
0.35 to 0.80
Estimation Comments [Not Specified]
4.Primary Outcome
Title PFS-IRF Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
3.19
(2.56 to 4.76)
5.72
(4.17 to 8.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0117
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.40 to 0.90
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 159 326
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
11.9
(7.35 to 18.03)
27.3
(22.54 to 32.48)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.90
Confidence Interval (2-Sided) 95%
1.68 to 5.01
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 158 325
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
13.3
(8.42 to 19.60)
33.2
(28.13 to 38.64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.39
Confidence Interval (2-Sided) 95%
2.02 to 5.71
Estimation Comments [Not Specified]
7.Secondary Outcome
Title ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 164 336
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
5.5
(2.54 to 10.16)
25.6
(21.01 to 30.61)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 6.15
Confidence Interval (2-Sided) 95%
2.99 to 12.66
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included Global participants with a confirmed response (CR or PR).
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 19 89
Median (95% Confidence Interval)
Unit of Measure: months
6.28 [1] 
(4.67 to NA)
NA [1] 
(NA to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0051
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.23
Confidence Interval (2-Sided) 95%
0.08 to 0.70
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included Global participants with a confirmed response (CR or PR).
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 21 108
Median (95% Confidence Interval)
Unit of Measure: months
6.28 [1] 
(4.86 to NA)
NA [1] 
(NA to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0048
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.30
Confidence Interval (2-Sided) 95%
0.12 to 0.73
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included Global participants with a confirmed response (CR or PR).
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 9 86
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(5.39 to NA)
13.08 [1] 
(13.08 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4187
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.16 to 2.15
Estimation Comments [Not Specified]
11.Secondary Outcome
Title PFS-IRF Per HCC mRECIST in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
4.24
(3.98 to 5.45)
6.83
(5.72 to 7.69)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.46 to 0.74
Estimation Comments [Not Specified]
12.Secondary Outcome
Title PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
2.89
(2.76 to 4.17)
7.06
(5.68 to 8.44)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.45
Confidence Interval (2-Sided) 95%
0.36 to 0.57
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
5.59
(4.21 to 7.72)
8.57
(6.83 to 9.86)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0105
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.53 to 0.92
Estimation Comments [Not Specified]
14.Secondary Outcome
Title TTP-IRF Per HCC mRECIST in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
5.55
(4.21 to 7.69)
8.28
(6.80 to 9.86)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0063
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.52 to 0.90
Estimation Comments [Not Specified]
15.Secondary Outcome
Title TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
3.98
(2.83 to 4.30)
8.54
(6.93 to 9.92)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.35 to 0.57
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Overall Survival by Baseline AFP in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Mean (95% Confidence Interval)
Unit of Measure: months
AFP <400 ng/mL Number Analyzed 104 participants 210 participants
13.93 [1] 
(11.73 to NA)
NA [1] 
(NA to NA)
AFP >/=400 ng/mL Number Analyzed 61 participants 126 participants
9.10 [1] 
(5.75 to NA)
12.78 [1] 
(10.15 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.32 to 0.78
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0879
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.42 to 1.06
Estimation Comments [Not Specified]
17.Secondary Outcome
Title PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
AFP <400 ng/mL Number Analyzed 104 participants 210 participants
4.40
(4.01 to 6.21)
8.28
(6.83 to 11.04)
AFP >/=400 ng/mL Number Analyzed 61 participants 126 participants
4.14
(2.76 to 5.26)
5.19
(3.94 to 6.77)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.37 to 0.68
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2159
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.53 to 1.15
Estimation Comments [Not Specified]
18.Secondary Outcome
Title PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
AFP <400 ng/mL Number Analyzed 104 participants 210 participants
3.98
(2.79 to 5.62)
8.41
(7.06 to 9.66)
AFP >/=400 ng/mL Number Analyzed 61 participants 126 participants
2.79
(1.58 to 3.98)
5.42
(4.17 to 6.90)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.42
Confidence Interval (2-Sided) 95%
0.31 to 0.57
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.51
Confidence Interval (2-Sided) 95%
0.35 to 0.73
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Time to Deterioration (TTD) in the Global Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 165 336
Median (95% Confidence Interval)
Unit of Measure: months
Physical Functioning
4.86
(3.48 to 6.24)
13.14 [1] 
(9.69 to NA)
Role Functioning
3.58
(2.20 to 5.98)
9.13 [1] 
(6.51 to NA)
GHS/QoL
3.58
(3.02 to 6.97)
11.24 [1] 
(5.98 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
0.39 to 0.73
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.46 to 0.84
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Sorafenib - Global, Atezolizumab + Bevacizumab - Global
Comments 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.46 to 0.85
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Percentage of Participants With Adverse Events (AEs) in the Global Population
Hide Description 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 40 months)
Outcome Measure Data Not Reported
21.Secondary Outcome
Title Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population
Hide Description [Not Specified]
Time Frame Post-dose on Day 1 of Cycle 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 309
Mean (Standard Deviation)
Unit of Measure: micrograms/milliliter (mcg/mL)
398  (132)
22.Secondary Outcome
Title Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population
Hide Description [Not Specified]
Time Frame Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 329
Mean (Standard Deviation)
Unit of Measure: mcg/mL
Pre-dose Cycle 2, Day 1 Number Analyzed 298 participants
79.2  (50.2)
Pre-dose Cycle 3, Day 1 Number Analyzed 41 participants
101  (55.4)
Pre-dose Cycle 4, Day 1 Number Analyzed 263 participants
131  (63.7)
Pre-dose Cycle 8, Day 1 Number Analyzed 134 participants
145  (61.7)
Pre-dose Cycle 12, Day 1 Number Analyzed 153 participants
168  (82.9)
Pre-dose Cycle 16, Day 1 Number Analyzed 124 participants
167  (65.0)
23.Secondary Outcome
Title Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population
Hide Description [Not Specified]
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Atezolizumab + Bevacizumab - Global
Hide Arm/Group Description:
Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 329
Measure Type: Number
Unit of Measure: percentage of participants
Baseline Number Analyzed 316 participants
2.2
Post-baseline Number Analyzed 318 participants
29.6
24.Secondary Outcome
Title Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 60 130
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
6.7
(1.85 to 16.20)
24.6
(17.49 to 32.94)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0036
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.60
Confidence Interval (2-Sided) 95%
1.53 to 13.86
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 59 128
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
8.5
(2.81 to 18.68)
29.7
(21.94 to 38.40)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0013
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.71
Confidence Interval (2-Sided) 95%
1.72 to 12.87
Estimation Comments [Not Specified]
26.Secondary Outcome
Title ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
4.9
(1.03 to 13.71)
21.1
(14.47 to 28.97)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0052
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 5.05
Confidence Interval (2-Sided) 95%
1.47 to 17.39
Estimation Comments [Not Specified]
27.Secondary Outcome
Title Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included China participants with a confirmed response (CR or PR).
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 4 32
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(4.86 to NA)
NA [1] 
(8.15 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4581
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
0.02 to 5.85
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included China participants with a confirmed response (CR or PR).
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 5 38
Median (95% Confidence Interval)
Unit of Measure: months
4.86 [1] 
(4.47 to NA)
NA [1] 
(8.15 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0100
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.08
Confidence Interval (2-Sided) 95%
0.01 to 0.91
Estimation Comments Lower limit: <0.01
29.Secondary Outcome
Title Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included China participants with a confirmed response (CR or PR).
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 3 28
Median (95% Confidence Interval)
Unit of Measure: months
5.55 [1] 
(4.17 to NA)
NA [1] 
(NA to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3477
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.33
Confidence Interval (2-Sided) 95%
0.03 to 3.69
Estimation Comments [Not Specified]
30.Secondary Outcome
Title PFS-IRF Per HCC mRECIST in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
3.19
(2.56 to 4.76)
5.72
(4.17 to 8.11)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0103
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.40 to 0.89
Estimation Comments [Not Specified]
31.Secondary Outcome
Title PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
2.83
(2.73 to 3.98)
5.55
(4.21 to 8.34)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.33 to 0.71
Estimation Comments [Not Specified]
32.Secondary Outcome
Title Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
4.14
(2.76 to 10.15)
7.00
(5.45 to 9.49)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0927
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
0.43 to 1.07
Estimation Comments [Not Specified]
33.Secondary Outcome
Title TTP-IRF Per HCC mRECIST in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
4.14
(2.76 to 10.15)
7.00
(5.45 to 9.49)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0861
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.43 to 1.06
Estimation Comments [Not Specified]
34.Secondary Outcome
Title TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
2.83
(2.79 to 4.17)
6.83
(5.32 to 9.33)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.33 to 0.74
Estimation Comments [Not Specified]
35.Secondary Outcome
Title Time to Deterioration (TTD) in the China Population
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
Arm/Group Title Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 61 133
Median (95% Confidence Interval)
Unit of Measure: months
Physical Functioning
5.62 [1] 
(2.10 to NA)
13.14 [1] 
(9.69 to NA)
Role Functioning
NA [1] 
(2.14 to NA)
NA [1] 
(7.20 to NA)
GHS/QoL
3.58
(1.48 to 9.82)
9.76 [1] 
(6.24 to NA)
[1]
NA = not estimable due to the limited number of events observed
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Physical Functioning: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0035
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.45
Confidence Interval (2-Sided) 95%
0.26 to 0.78
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments Role Functioning: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2214
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.42 to 1.23
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Sorafenib - China, Atezolizumab + Bevacizumab - China
Comments GHS/QoL: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0135
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
0.32 to 0.88
Estimation Comments [Not Specified]
36.Secondary Outcome
Title Percentage of Participants With Adverse Events (AEs) in the China Population
Hide Description 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 40 months)
Outcome Measure Data Not Reported
37.Secondary Outcome
Title Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population
Hide Description [Not Specified]
Time Frame Post-dose on Day 1 of Cycle 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 85
Mean (Standard Deviation)
Unit of Measure: mcg/mL
456  (153)
38.Secondary Outcome
Title Trough Serum Concentration (Cmin) of Atezolizumab in the China Population
Hide Description [Not Specified]
Time Frame Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 132
Mean (Standard Deviation)
Unit of Measure: mcg/mL
Pre-dose Cycle 2, Day 1 Number Analyzed 87 participants
92.6  (65.7)
Pre-dose Cycle 3, Day 1 Number Analyzed 4 participants
105  (36.8)
Pre-dose Cycle 4, Day 1 Number Analyzed 80 participants
143  (61.4)
Pre-dose Cycle 8, Day 1 Number Analyzed 11 participants
177  (61.9)
Pre-dose Cycle 12, Day 1 Number Analyzed 20 participants
201  (97.6)
Pre-dose Cycle 16, Day 1 Number Analyzed 13 participants
208  (79.4)
39.Secondary Outcome
Title Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population
Hide Description [Not Specified]
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Atezolizumab + Bevacizumab - China
Hide Arm/Group Description:
Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Overall Number of Participants Analyzed 132
Measure Type: Number
Unit of Measure: percentage of participants
Baseline Number Analyzed 90 participants
1.1
Post-baseline Number Analyzed 89 participants
20.2
Time Frame Baseline up to clinical cut off date (CCOD) of 31 August, 2020 (up to approximately 30 months)
Adverse Event Reporting Description All-cause mortality is reported for deaths that occurred during the study based on the ITT population, which included all randomized participants. Serious and other adverse events were reported based on the safety population, which included all randomized participants who received any amount of study drug with participants grouped according to the treatment the participant actually received. Global and China extension periods were analyzed separately.
 
Arm/Group Title Sorafenib - Global Atezolizumab + Bevacizumab - Global Sorafenib - China Atezolizumab + Bevacizumab - China
Hide Arm/Group Description Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
All-Cause Mortality
Sorafenib - Global Atezolizumab + Bevacizumab - Global Sorafenib - China Atezolizumab + Bevacizumab - China
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   99/165 (60.00%)      179/336 (53.27%)      38/61 (62.30%)      61/133 (45.86%)    
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Sorafenib - Global Atezolizumab + Bevacizumab - Global Sorafenib - China Atezolizumab + Bevacizumab - China
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   51/156 (32.69%)      160/329 (48.63%)      12/58 (20.69%)      47/132 (35.61%)    
Blood and lymphatic system disorders         
Anaemia † 1  2/156 (1.28%)  2 5/329 (1.52%)  7 1/58 (1.72%)  1 3/132 (2.27%)  3
Immune thrombocytopenia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Thrombocytopenia † 1  2/156 (1.28%)  2 2/329 (0.61%)  4 2/58 (3.45%)  2 1/132 (0.76%)  3
Cardiac disorders         
Acute coronary syndrome † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Acute myocardial infarction † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Atrial fibrillation † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Cardiac arrest † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Cardiac failure † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Myocardial infarction † 1  0/156 (0.00%)  0 3/329 (0.91%)  3 0/58 (0.00%)  0 1/132 (0.76%)  1
Congenital, familial and genetic disorders         
Hydrocele † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Ear and labyrinth disorders         
Hypoacusis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Endocrine disorders         
Addison's disease † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hypophysitis † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Eye disorders         
Blindness unilateral † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Gastrointestinal disorders         
Abdominal distension † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 2/132 (1.52%)  2
Abdominal pain † 1  2/156 (1.28%)  3 2/329 (0.61%)  2 1/58 (1.72%)  1 1/132 (0.76%)  1
Abdominal pain upper † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 2/132 (1.52%)  2
Anal fissure † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Ascites † 1  1/156 (0.64%)  1 9/329 (2.74%)  13 0/58 (0.00%)  0 3/132 (2.27%)  5
Colitis † 1  1/156 (0.64%)  1 4/329 (1.22%)  4 0/58 (0.00%)  0 0/132 (0.00%)  0
Diarrhoea † 1  1/156 (0.64%)  1 5/329 (1.52%)  5 0/58 (0.00%)  0 0/132 (0.00%)  0
Duodenal ulcer † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Dysphagia † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Gastric mucosal lesion † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Gastric ulcer haemorrhage † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Gastric ulcer perforation † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Gastric varices haemorrhage † 1  1/156 (0.64%)  1 3/329 (0.91%)  3 0/58 (0.00%)  0 1/132 (0.76%)  1
Gastrointestinal haemorrhage † 1  3/156 (1.92%)  4 10/329 (3.04%)  10 0/58 (0.00%)  0 2/132 (1.52%)  2
Gastrointestinal necrosis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Haematemesis † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Haemoperitoneum † 1  2/156 (1.28%)  2 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Hiatus hernia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Ileus † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Immune-mediated enterocolitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Incarcerated umbilical hernia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Large intestinal haemorrhage † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Melaena † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Mesenteric vein thrombosis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Mouth haemorrhage † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Oesophageal haemorrhage † 1  0/156 (0.00%)  0 3/329 (0.91%)  3 0/58 (0.00%)  0 0/132 (0.00%)  0
Oesophageal stenosis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Oesophageal varices haemorrhage † 1  1/156 (0.64%)  1 9/329 (2.74%)  10 0/58 (0.00%)  0 1/132 (0.76%)  1
Pancreatitis † 1  2/156 (1.28%)  2 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Rectal haemorrhage † 1  1/156 (0.64%)  1 3/329 (0.91%)  4 0/58 (0.00%)  0 0/132 (0.00%)  0
Umbilical hernia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Upper gastrointestinal haemorrhage † 1  2/156 (1.28%)  2 5/329 (1.52%)  5 1/58 (1.72%)  1 5/132 (3.79%)  5
Varices oesophageal † 1  0/156 (0.00%)  0 3/329 (0.91%)  3 0/58 (0.00%)  0 0/132 (0.00%)  0
Vomiting † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
General disorders         
Death † 1  2/156 (1.28%)  2 1/329 (0.30%)  1 1/58 (1.72%)  1 1/132 (0.76%)  1
Fatigue † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
General physical health deterioration † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Multiple organ dysfunction syndrome † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Pyrexia † 1  2/156 (1.28%)  2 11/329 (3.34%)  15 1/58 (1.72%)  1 4/132 (3.03%)  7
Hepatobiliary disorders         
Acute hepatic failure † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Autoimmune hepatitis † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Bile duct stone † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Cholangitis † 1  1/156 (0.64%)  1 4/329 (1.22%)  6 0/58 (0.00%)  0 0/132 (0.00%)  0
Cholecystitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Drug-induced liver injury † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatic cirrhosis † 1  2/156 (1.28%)  2 3/329 (0.91%)  3 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatic failure † 1  2/156 (1.28%)  2 3/329 (0.91%)  3 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatic function abnormal † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 5/132 (3.79%)  5
Hepatic pain † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatobiliary disease † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatorenal failure † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatorenal syndrome † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hyperbilirubinaemia † 1  1/156 (0.64%)  1 3/329 (0.91%)  3 0/58 (0.00%)  0 0/132 (0.00%)  0
Hypertransaminasaemia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Jaundice † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Liver injury † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 1/58 (1.72%)  1 0/132 (0.00%)  0
Immune system disorders         
Anaphylactic reaction † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Cytokine release syndrome † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Infections and infestations         
Abscess limb † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Biliary tract infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Bronchitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Burkholderia pseudomallei infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Cellulitis † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Device related infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Empyema † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Escherichia sepsis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Gastroenteritis † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
Haemophilus infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatitis E † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Herpes simplex encephalitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Lower respiratory tract infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Peritoneal abscess † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Peritonitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Peritonsillar abscess † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 1/58 (1.72%)  1 0/132 (0.00%)  0
Pneumonia † 1  1/156 (0.64%)  1 5/329 (1.52%)  5 0/58 (0.00%)  0 3/132 (2.27%)  3
Post procedural infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Sepsis † 1  0/156 (0.00%)  0 8/329 (2.43%)  9 0/58 (0.00%)  0 1/132 (0.76%)  1
Septic shock † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
Skin infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Tooth infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Tuberculosis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Upper respiratory tract infection † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Urinary tract infection † 1  0/156 (0.00%)  0 3/329 (0.91%)  3 0/58 (0.00%)  0 1/132 (0.76%)  1
Urosepsis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Injury, poisoning and procedural complications         
Acetabulum fracture † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Compression fracture † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Fall † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Hip fracture † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Humerus fracture † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Infusion related reaction † 1  0/156 (0.00%)  0 4/329 (1.22%)  6 0/58 (0.00%)  0 0/132 (0.00%)  0
Pelvic fracture † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Spinal compression fracture † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 0/132 (0.00%)  0
Investigations         
Alanine aminotransferase increased † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Amylase increased † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Aspartate aminotransferase increased † 1  1/156 (0.64%)  1 4/329 (1.22%)  4 0/58 (0.00%)  0 1/132 (0.76%)  1
Blood bilirubin increased † 1  2/156 (1.28%)  2 5/329 (1.52%)  5 1/58 (1.72%)  1 1/132 (0.76%)  1
General physical condition abnormal † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Granulocyte count decreased † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Lipase increased † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Liver function test increased † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Platelet count decreased † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
Metabolism and nutrition disorders         
Decreased appetite † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Diabetes mellitus † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Diabetes mellitus inadequate control † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hyperammonaemia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hyperglycaemia † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hyperglycaemic hyperosmolar nonketotic syndrome † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hyperkalaemia † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
Hypoalbuminaemia † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 1/58 (1.72%)  1 0/132 (0.00%)  0
Hypoglycaemia † 1  1/156 (0.64%)  1 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
Hypokalaemia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hyponatraemia † 1  2/156 (1.28%)  2 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hypoproteinaemia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Lactic acidosis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Metabolic acidosis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Type 2 diabetes mellitus † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Musculoskeletal and connective tissue disorders         
Arthralgia † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 1/58 (1.72%)  1 0/132 (0.00%)  0
Autoimmune arthritis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Back pain † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 1/132 (0.76%)  1
Groin pain † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Muscular weakness † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Myositis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Pathological fracture † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Tendonitis † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Chronic myeloid leukaemia † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Gastric cancer † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 0/58 (0.00%)  0 0/132 (0.00%)  0
Neoplasm † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Oesophageal squamous cell carcinoma † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Tumour haemorrhage † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Tumour rupture † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Nervous system disorders         
Altered state of consciousness † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Cerebral haemorrhage † 1  1/156 (0.64%)  1 0/329 (0.00%)  0 1/58 (1.72%)  1 0/132 (0.00%)  0
Cerebral infarction † 1  0/156 (0.00%)  0 2/329 (0.61%)  2 0/58 (0.00%)  0 2/132 (1.52%)  2
Cerebrovascular accident † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Encephalopathy † 1  1/156 (0.64%)  1 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Epilepsy † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 1/132 (0.76%)  1
Haemorrhage intracranial † 1  0/156 (0.00%)  0 1/329 (0.30%)  1 0/58 (0.00%)  0 0/132 (0.00%)  0
Hepatic encephalopathy † 1  3/156 (1.92%)  3 4/329 (1.22%)  4 0/58 (0.00%)  0