Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review

Table 1 Characteristics of the two ongoing and two completed clinical trials

Ongoing clinical trials	La Roche[14], 2020	Hack et al[15], 2020
Country of enrollment	Italy	170 sites in 25 countries (Asia)
Study design	Single-arm, multi-Center, randomized clinical control trial	Multi-center randomized open-label, clinical control trial
Study phase	IIIb	III
Study quality	NA (study is still ongoing)	NA (study is still ongoing)
Intervention	Atezolizumab plus bevacizumab	Atezolizumab plus bevacizumab
	Dose: atezolizumab 1200 mg IV infusion q3w + bevacizumab 15 mg/kg IV Q3W	Dose: atezolizumab 1200 mg every 3 wk + bevacizumab 15 mg/every 3 wk
Control	Standard of care	Active surveillance
	No specifications for control arm reported
Number of patients	150	662
Intervention/control	Intervention not specified	Intervention 501
	Control: Not specified	Control: 119
Median age (range)	Not reported	Not reported
Intervention/control	Study included individuals > 18 yr	Study included individuals > 18 yr
-Duration of follow-up in mo	Not reported	Intervention: 8.6 mo
Intervention/control		Control: 6.5 mo
Types of outcomes reported	Overall survival	Overall survival
	Median progression-free survival	Median progression-free survival
	Grade 3-5 adverse events	Grade 3 or 4 adverse events
	Disease control	Disease control
	Objective response rate
	Time to progression
	Duration of response
	Post-progression survival
Data that could not be evaluated/data missing	NA (study is still ongoing)	NA (study is still ongoing)
Completed studies	Finn et al[12], 2020	Lee et al[16], 2020
Country/ies of Enrollment	111 sites in 17 countries, which include the United States, China, Japan, Germany, France, South Korea, Russia, Canada, and Taiwan	26 sites in 7 countries, which include the United States, Japan, South Korea, Taiwan, Australia, and New Zealand
Study design	Open-label, randomized clinical trial	Multi-arm study with five cohorts
		However, only the two cohorts focusing on hepatocellular carcinoma, Groups A and F, are described here in this study
Phase	III	Ib
Study Quality	Low risk of bias	Low risk of bias
Intervention	Atezolizumab plus bevacizumab	Atezolizumab plus bevacizumab
	Dose: 1200 mg atezolizumab + 15 mg/kg of bevacizumab IV q3w	Dose: 1200 mg atezolizumab + 15 mg/kg of bevacizumab IV q3w
Control	Sorafenib monotherapy	Atezolizumab monotherapy
	Dose: 400 mg sorafenib PO BID	Dose: 1200 mg atezolizumab
Number of patients	501	403
Intervention/control	Intervention: 336	Group A1: 104
	Control: 165	Group F+: 60
		Control:
		59 included in efficacy analysis1
		58 included in safety analysis
		1 discontinued before receiving any treatment due to elevated alkaline phosphatase concentrations1
Median duration of follow-up (mo, [IQR])	Overall: 8.6 mo	Overall follow-up not given, see stratified data below
Intervention/control		Group A1: 12.4 (IQR 8.0-16.2)
	Intervention: 8.9	Group F+: 6.6 (IQR 5.5-8.5)
		Control: 6.7 (IQR 4.2-8.2)
	Control: 8.1
Primary outcomes reported	Mortality rates	Mortality rates
	Hazard ratio for death	Hazard ratio for death
Secondary Outcomes reported	Overall survival	Overall survival
	Median progression free survival	Median progression free survival
	Grade 3-5 adverse events	Grade 3-4 adverse events
	Disease control	Disease control
	Objective response rate	Objective response rate
	Time to progression	Time to progression
	Duration of response	Duration of response
	Post-progression survival	Post-progression survival

¹Group A: Patients with hepatitis B virus DNA of 500 IU/mL or less and ongoing anti-hepatitis B virus treatment for at least 3 mo before and at study entry; patients enrolled in Group F must have had hepatitis B virus DNA of 500 IU/mL or less measured up to 28 d before study entry and anti-hepatitis B virus treatment for at least 14 d before study entry. +: Group F: Patients in Child-Pugh class A, life expectancy of 3 mo and platelet count or > 75000/μL. NA: Not applicable.

Table 2 Baseline characteristics of patients among the included studies

	Finn et al[12], 2020		Lee et al[16], 2020
	Interventional arm	Control arm	Interventional arm		Control arm
	Atezolizumab-bevacizumab combination therapy	Sorafenib monotherapy	Atezolizumab-bevacizumab combination therapy given in both Arms A and F		Atezolizumab monotherapy
			Group A	Group F+
	n = 336	n = 165	n = 104	n = 60	n = 59
Median age (IQR), yr	64 (56-71)	66 (59-71)	62 (23-82)	60 (22-82)	63 (23-85)
Gender, n (%)
Male	277 (82)	137 (83)	84 (81)	54 (90)	49 (83)
Female	59 (18)	28 (17)	20 (19)	6 (10)	10 (17)
Race, n (%)
White	123 (37)	52 (32)	20 (19)	14 (23)	9 (15)
Asian	188 (56)	96 (58)	75 (72)	45 (75)	47 (80)
Black or African American	6 (1.8)	4 (2.4)	7 (7)	1 (2)	2 (3)
Native Hawaiian or other Pacific Islander	0 (0)	0 (0)	0 (0)	0 (0)	1 (2)
Unknown	19 (6)	12 (7)	2 (2)	0 (0)	0 (0)
Geographic region, n (%)
Asian excluding Japan	133 (40)	68 (41)	59 (57)	39 (65)	39 (66)
Rest of the world (United States, Australia, New Zealand, and Japan)	203 (60)	97 (59)	45 (43)	21 (35)	20 (34)
Child Pugh, n (%)
Child Pugh A5	239 (72)	121 (73)	77 (74)	43 (72)	42 (71)
Child Pugh A6	94 (28)	44 (27)	21 (20)	17 (28)	17 (29)
Child Pugh A7	0 (0)	0	6 (6)	17 (28)	17 (29)
Child Pugh B	1 (< 1)	0 (0)	NA	NA	NA
ECOG performance status, n (%)
ECOG 0	209 (62)	103 (62)	52 (50)	27 (45)	25 (42)
ECOG 1	127 (38)	62 (38)	52 (50)	33 (55)	34 (58)
BCLC, n (%)
BCLC stage A (early)	8 (2)	6 (4)	0 (0)	0 (0)	2 (3)
BCLC stage B (intermediate)	52 (15)	26 (16)	10 (10)	6 (10)	4 (7)
BCLC stage C (advanced)	276 (82)	133 (81)	94 (90)	54 (90)	53 (90)
Alpha-fetoprotein > 400 ng per milliliter	126 (38%)	61 (37%)	37 (36%)	18 (30%)	19 (32%)
Macrovascular invasion	129 (38%)	71 (43%)	55 (53%)	20 (33%)	25 (42%)
Extrahepatic spread	212 (63%)	93 (56%)	91 (88%)	47 (78%)	50 (85%)
Hepatitis B	164 (49%)	76 (46%)	51 (49%)	34 (57%)	32 (54%)
Hepatitis C	72 (21%)	36 (22%)	31 (30%)	11 (18%)	10 (17%)
Non-viral	100 (30%)	85 (52%)	22 (21%)	15 (25%)	17 (29%)
Alcohol use, n (%)
Previous	166 (50)	79 (48)	58 (56)	39 (65)	32 (54)
Never	121 (36)	61 (37)	32 (31)	14 (23)	21 (36)
Current	48 (14)	25 (15)	14 (13)	7 (12)	6 (10)
Varices at baseline	88 (26%)	43 (26%)	NA	NA	NA
Varices treated at baseline	36 (11%)	23 (14%)	NA	NA	NA
PD-L1 status, n (%)	124	58	NA	NA	NA
TC and IC < 1%	45 (36)	25 (43)	25 (24)	15 (25)	18 (31)
TC or IC ≥ 1%	79 (64)	33 (57)	61 (59)	28 (47)	34 (58)
TC ≥ 5% or IC ≥ 5%	46 (37)	17 (29)	37 (36)	8 (13)	16 (27)
TC ≥ 10% or IC ≥ 10%	12 (10)	5 (9)	30 (29)	5 (8)	6 (10)
Data missing	NA	NA	18 (17)	17 (28)	8 (14)
Prior local therapy for HCC, n (%)
At least one treatment	161 (48)	85 (52)	NA	NA	NA
Transarterial chemoembolization	130 (39)	70 (42)	NA	NA	NA
Radiofrequency ablation	47 (14)	24 (15)	NA	NA	NA
Prior radiotherapy	34 (10)	17 (10)	NA	NA	NA

BCLC: Barcelona Clinic Liver Cancer stage; ECOG: Eastern Cooperative Oncology Group; HCC: Hepatocellular carcinoma; IC: Immune cells; IQR: Interquartile range; NA: Not available; PD-L1: Programmed death-ligand 1; TC: Tumor cells.

Table 3 Summary of the efficacy and safety findings

Ref.	Finn et al[12], 2020		Lee et al[16], 2020
Schemes	Atezolizumab-bevacizumab combination therapy	Sorafenib monotherapy	Atezolizumab-bevacizumab combination therapy given in both Arm A and F		Atezolizumab monotherapy
Total patients			Group A	Group F+
	n = 336	n = 165	n = 104	n = 60	n = 59
Primary efficacy outcomes
Mortality
n (%)	96 (28.6)	65 (39.4)	16 (27)	0 (0)	18 (31)
Two-tail P value	P = 0.0033	P = 0.0033	No P value reported	No P value reported	No P value reported
HR for disease progression, CI	0.59, 95%CI: 0.47-0.76	Not applicable	NA	NA	NA
Two-tail P value	P < 0.001
HR for death, CI	0.58, 95%CI: 0.42-0.79	NA	NA	NA	NA
Two-tail P value	P < 0.001
HR for progression-free survival, CI	NA	NA	0.55, 80%CI: 0.40-0.74		NA
Two-tail P value			P = 0.011
Secondary efficacy outcomes tumor survival and progression of disease
Overall/survival rate, n (%)	n not explicitly reported	n not explicitly reported	57 (55)	16 (27)	18 (31)
n (%)	-67.2	-54.6
95%CI			CI not reported	CI not reported	CI not reported
	61.3-73.1	45.2-64
Median overall survival in mo	Not estimable	13.2 mo	17.1 mo	Median overall survival was not reached	Median overall survival was not reached
95%CI
		(10.4 to not estimable)	(13.8 to not estimable)	(8.3 to not estimable)	(8.2 to not estimable)
6 mo overall survival rates			NA	NA	NA
95%CI	84.80%	72.20%
	80.9-88.7	80.9-88.7
12 mo overall survival rates	67.20%	54.60%	NA	NA	NA
95%CI	61.3-73.1	45.2-64
Median progression-free survival (mo), (95%CI)	6.8 mo	4.3 mo	7.3 mo	5.6 mo	3.4 mo
	(5.7-8.3)	(4.0-5.6)	(5.4-9.9)	(3.6-7.4)	(1.9-5.2)
Overall confirmed objective response				n not explicitly reported (20%)	n not explicitly reported (17%)
n (%) as per RECIST 1.1				(11-32)	(8-29)
95%CI	89 (27.3%)	19 (11.9%)	37 (36%)
	(22.5-32.5)	(7.4-18)	(26-46)
Confirmed objective response-complete response as per RECIST 1.1, n (%)	18 (5.5)	0 (0)	12 (12)	1 (2)	3 (5)
Confirmed objective response-Partial response as per RECIST 1.1, n (%)	71 (21.8)	19 (11.9)	25 (24)	11 (18)	7 (12)
Stable disease n (%) as per RECIST 1.1	151 (46.3)	69 (43.4)	37 (36)	28 (47)	19 (32)
Progressive disease
n (%) as per RECIST 1.1	64 (19.6)	39 (24.5)	25 (24)	17 (28)	25 (42)
Disease control rate, n (%)	240 (73.6)	88 (55.3)	74 (71)	40 (67)	29 (49)
Ongoing objective response at data cut off, n (%)	77/89 (86.5)	13/19 (68.4)	NA	NA	NA
Safety outcomes (adverse events)
Overall patients with an adverse event from any cause, n (%)	323 (98.2)	154 (98.7)	100 (96)	57 (95)	52 (90)
Treatment-related serious adverse events, n (%)	125 (38)	48 (30.8)	25 (24)	7 (12)	2 (3)
Treatment-related mortality	161 deaths (%)		3 (3%)	0 (%)	NA
	It was not explicitly stated how many deaths there were in relation to treatment in either intervention or control arm1
Adverse events leading to dose modifications, n (%)	163 (49.5)	95 (60.9)	50 (48)	9 (15)	5 (9)
Adverse events leading to withdrawal from any trial drug, n (%)	51 (15.5)	16 (10.3)	18 (17)	6 (10)	0 (0)
Number of participants with Grade 3 and above, n (%)	5-15 (4.6)	9 (5.8)	55 (53)	22 (37)	8 (14)
Types of Grade 3-4 adverse events
Adverse events	Note: All stratified data reported below are Grade 3 or 4		Note: All stratified data reported below are Grade 3, except increased aspartate aminotransferase (note stratification)
Hypertension, n (%)	50 (15.2)	19 (12.2)	15 (14)	3 (5)	1 (1)
Decreased appetite, n (%)	4 (1.2)	6 (3.8)	1 (1)	0 (0)	0 (0)
Fatigue, n (%)	8 (2.4)	5 (3.2)	1 (1)	0 (0)	0 (0)
Pyrexia, n (%)	4 (1.2)	2 (1.3)	2 (2)	0 (0)	0 (0)
Rash, n (%)	0 (0)	4 (2.6)	0 (0)	0 (0)	0 (0)
Diarrhea, n (%)	6 (1.8)	8 (5.1)	3 (3)	1 (2)	0 (0)
Abdominal pain, n (%)	4 (1.2)	4 (2.6)	4 (4)	0 (0)	0 (0)
Constipation, n (%)	0 (0)	0 (0)	1 (1)	0 (0)	0 (0)
Cough, n (%)	0 (0)	1 (0.6)	0 (0)	0 (0)	0 (0)
Nausea, n (%)	1 (0.3)	1 (0.6)	NA	NA	NA
Weight decrease, n (%)	0 (0)	1 (0.6)	NA	NA	NA
Epistaxis, n (%)	0 (0)	1 (0.6)	NA	NA	NA
Asthenia, n (%)	1 (0.3)	4 (2.6)	NA	NA	NA
Infusion-related reaction, n (%)	8 (2.4)	0 (0)	NA	NA	NA
Palmar-Plantar erythrodysesthesia syndrome, n (%)	0 (0)	13 (8.3)	NA	NA	NA
Proteinuria, n (%)	10 (3)	1 (0.6)	7 (7)	3 (5)	0 (0)
Increased aspartate aminotransferase, n (%)	23 (7.0)	8 (5.1)	Grade 3: 3 (3)	2 (3)	2 (3)
			Grade 4: 2 (2)
Increased alanine aminotransferase, n (%)	12 (3.6)	2 (1.3)	NA	NA	NA
Blood bilirubin increase, n (%)	8 (2.4)	10 (6.4)	NA	NA	NA
Decreased platelet count, n (%)	11 (3.3)	2 (1.3)	5 (5)	0 (0)	0 (0)
Pancreatitis, n (%)	1 (0.3)	2 (1.3)	NA	NA	NA
Hepatic Encephalopathy, n (%)	2 (0.6)	2 (1.3)	NA	NA	NA
Pulmonary Embolism, n (%)	3 (0.9)	2 (1.3)	NA	NA	NA
Cholangitis, n (%)	4 (1.2)	1 (0.6)	NA	NA	NA
Acute kidney failure, n (%)	1 (0.3)	3 (1.9)	NA	NA	NA
Gastrointestinal hemorrhage, n (%)	4 (1.2)	3 (1.9)	NA	NA	NA
Esophageal varices hemorrhage, n (%)	6 (1.8)	1 (0.6)	NA	NA	NA
Upper gastrointestinal hemorrhage, n (%)	2 (0.6)	2 (1.3)	NA	NA	NA
Asthenia, n (%)	1 (0.3)	4 (2.6)	NA	NA	NA
Types of Grade 5 adverse events
Grade 5 adverse events, n (%)	15 (4.6)	9 (5.8)	0 (0)	0 (0)	0 (0)
	Not stratified1	Not stratified1
Not evaluable/data missing
Not evaluable, n (%)	8 (2.5)	14 (8.8)	NA	NA	NA
Data missing, n (%)	14 (4.3)	18 (11.3)	NA	NA	NA

¹Group A: Patients with hepatitis B virus DNA of 500 IU/mL or less and ongoing anti-hepatitis B virus treatment for at least 3 mo before and at study entry. Patients enrolled in group F must have had hepatitis B virus DNA of 500 IU/mL or less measured up to 28 d before study entry and anti-hepatitis B virus treatment for at least 14 d before study entry. +: Group F: Patients in Child-Pugh class A, life expectancy of 3 mo and platelet count or > 75000/μL; CI: Confidence interval; HR: Hazard ratio; NA: Not available.