Modified albumin-bilirubin predicted survival of unresectable hepatocellular carcinoma patients treated with immunotherapy

Table 1 Baseline characteristics of the unresectable hepatocellular carcinoma patients who received atezolizumab plus bevacizumab therapy, n (%)

Variables	Total, n = 83	mALBI 1+2a, n = 42	mALBI 2b+3, n = 41	P value
Age in yr, mean ± SD	60.6 ± 12.8	59.8 ± 14.0	61.5 ± 11.5	0.560
Male	67 (80.7)	34 (81.0)	33 (80.5)	0.960
ECOG-PS				0.680
0	78 (94.0)	40 (95.2)	38 (92.7)
1	5 (6.0)	2 (4.8)	3 (7.3)
Presence of cirrhosis	76 (91.6)	35 (83.3)	41 (100)	< 0.001
CTP A	58 (69.9)	35 (83.3)	23 (56.1)
CTP B	18 (21.7)	0 (0)	18 (43.9)
Etiology of disease
Viral hepatitis	53 (63.9)	27 (64.3)	26 (63.4)	0.930
NASH	23 (27.7)	11 (26.2)	12 (29.3)	0.750
Alcohol related	7 (8.4)	1 (2.4)	6 (14.6)	0.060
Others	1 (1.2)	1 (2.4)	0 (0)	1.000
BCLC staging
BCLC B	22 (26.5)	6 (14.3)	16 (39.0)	0.010
BCLC C	61 (73.5)	36 (85.7)	25 (61.0)
Macrovascular invasion	30 (36.1)	15 (35.7)	15 (36.6)	0.930
Extrahepatic metastasis	40 (48.2)	25 (59.5)	15 (36.6)	0.040
AFP in ng/mL, median (IQR)	339.0 (10.7, 6300.0)	581.5 (11.5, 6869.5)	339.0 (10.5, 9144.5)	0.880
Tumor size in cm, median (IQR)	5.3 (1.7, 12.0)	4.8 (1.7, 11.0)	5.6 (1.7, 14.3)	0.730
Portal vein invasion grade of 2/3/4	8 (26.7)/13 (43.3)/9 (30.0)	4 (26.7)/7 (46.7)/4 (26.7)	4 (26.7)/6 (40.0)/5 (33.3)	1.000
EHM bone/lymph node/lung/peritoneum	11 (27.5)/14 (35.0)/21 (52.5)/9 (22.5)	8 (32.0)/7 (28.0)/13 (52.0)/3 (12.0)	3 (20.0)/7 (46.7)/8 (53.3)/6 (40.0)	0.350
ALBI score, median (IQR)	-2.270 (-2.628 to -1.826)	-2.622 (-2.836 to -2.398)	-1.826 (-2.067 to -1.434)	< 0.001
mALBI grade				< 0.001
1: ≤ -2.60	23 (27.7)	23 (54.8)	0 (0)
2a: > -2.60 to ≤ -2.27	19 (22.9)	19 (45.2)	0 (0)
2b: > -2.27 to ≤ -1.39	32 (38.6)	0 (0)	32 (78.0)
3: > -1.39	9 (10.8)	0 (0)	9 (22.0)
Prior local therapy for HCC	62 (74.7)	33 (78.6)	29 (70.7)	0.410
Resection	22 (35.5)	17 (51.5)	5 (17.2)	0.005
Ablation	17 (27.4)	9 (27.3)	8 (27.6)	0.980
TACE	48 (77.4)	23 (69.7)	25 (86.2)	0.120
TARE	9 (14.5)	5 (15.2)	4 (13.8)	1.000
EBRT	19 (30.6)	11 (33.3)	8 (27.6)	0.620
Prior systemic therapy for HCC	10 (12.0)	4 (9.5)	6 (14.6)	0.460
Sorafenib	5 (50.0)	1 (25.0)	4 (66.7)	0.530
Lenvatinib	4 (40.0)	2 (50.0)	2 (33.3)	1.000
> 2 lines of systemic therapy	2 (20.0)	1 (25.0)	1 (16.7)	1.000
AB as first-line treatment	20 (24.1)	9 (21.4)	11 (26.8)	0.570
Combination of AB and other local therapy as first-line treatment	3 (3.6)	3 (7.1)	0 (0)	0.240
Resection/TACE/TARE/EBRT	0 (0)/0 (0)/0 (0)/3 (100)	0 (0)/0 (0)/0 (0)/3 (100.0)	0 (0)/0 (0)/0 (0)/0 (0)	0.240
Number of AB cycle, median (IQR)	4.0 (2.0, 9.0)	5.0 (4.0, 11.3)	3.0 (1.0, 4.5)	< 0.001

AB: Atezolizumab plus bevacizumab; AFP: Alpha fetoprotein; ALBI: Albumin-bilirubin; BCLC: Barcelona Clinic Liver Cancer; CTP: Child-Turcotte-Pugh; EBRT: External beam radiotherapy; ECOG-PS: Eastern Cooperative Oncology Group Performance Status; EHM: Extrahepatic metastasis; HCC: Hepatocellular carcinoma; IQR: Interquartile range; mALBI: Modified albumin-bilirubin; NASH: Nonalcoholic steatohepatitis; SD: Standard deviation; TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization.

Table 2 Efficacy outcomes of atezolizumab plus bevacizumab¹, n (%)

Variables	Total, n = 61	mALBI 1 + 2a, n = 39	mALBI 2b + 3, n = 22	P value
Complete response	4 (6.6)	3 (7.7)	1 (4.5)	1.000
Partial response	13 (21.3)	11 (28.2)	2 (9.1)	0.110
Stable disease	21 (34.4)	12 (30.8)	9 (40.9)	0.420
Objective response rate	17 (27.9)	14 (35.9)	3 (13.6)	0.060
Disease control rate	38 (62.3)	26 (66.7)	12 (54.5)	0.350
Progressive disease	23 (37.7)	13 (33.3)	10 (45.5)	0.350

¹The number of patients who had available data on treatment response evaluation were 61/83 patients (73.5%), and 22/83 patients (26.5%) had died prior to treatment response evaluation. mALBI: Modified albumin-bilirubin.

Table 3 Median overall survival and progression-free survival of unresectable hepatocellular carcinoma patients who received atezolizumab plus bevacizumab therapy stratified by liver function, tumor size, and tumor stage

Variables	No. of events/No. of patients	Median OS (95%CI), mo	P value	No. of events/No. of patients	Median OS (95%CI), mo	P value
A. Entire cohort, n = 83
CTP class			< 0.001			NE
CTP A	25/65	17 (-)		34/65	9.0 (5.1-12.9)
CTP B	14/18	2.0 (1.1-2.9)		3/18	NE
Tumor size in cm			0.790			0.130
≤ 5.0	21/41	12.0 (4.8-19.2)		21/41	7.0 (2.8-11.2)
> 5.0	18/42	NE		16/42	16.0 (6.5-25.5)
B. BCLC C group, n = 61	27/61	14.0 (-)		28/61	10.0 (0.5-19.5)
CTP class			< 0.001			0.810
CTP A	18/49	NE		26/49	10.0 (0.3-19.7)
CTP B	9/12	1.0 (0.1-2.5)		2/12	NE
Tumor size in cm			0.850			0.060
≤ 5.0	13/26	12.0 (3.4-20.6)		15/26	6.0 (2.5-9.5)
> 5.0	14/35	NE		13/35	24.0 (9.4-38.6)
With PV invasion, n = 30			0.140			0.030
No	12/31	NE		20/31	6.0 (3.2-8.8)
Yes	15/30	13.0 (2.0-24.0)		8/30	24.0 (-)
With EHM metastasis, n = 40			0.540			0.170
No	10/21	13.0 (0.1-27.3)		7/21	24 (-)
Yes	17/40	NE		21/40	6.0 (1.1-10.9)
C. BCLC B group, n = 22	12/22	11.0 (2.7-19.3)		9/22	8.0 (1.3-14.7)
CTP class			0.020			0.660
CTP A	7/16	11.0 (5.6-16.4)		8/16	8.0 (1.5-14.5)
CTP B	5/6	2.0 (0.8-3.2)		1/6	5.0 (-)
Tumor size in cm			0.490			0.140
≤ 5.0	8/15	11.0 (0.1-24.1)		6/15	9.0 (6.9-11.1)
> 5.0	4/7	7.0 (0.1-17.3)		3/7	5.0 (-)

CI: Confidence interval; BCLC: Barcelona Clinic Liver Cancer; CTP: Child-Turcotte-Pugh; EHM: Extrahepatic metastasis; NE: Not estimated; OS: Overall survival; PFS: Progression-free survival; PV: Pulmonary vein.

Table 4 Treatment after progression on atezolizumab plus bevacizumab therapy¹, n (%)

Treatment	Total, n = 37	mALBI 1 + 2a, n = 24	mALBI 2b + 3, n = 13	P value
Systemic therapy	32 (86.5)	22 (91.7)	10 (76.9)	0.320
TACE	4 (10.8)	4 (16.7)	0 (0)	0.280
EBRT	8 (21.6)	6 (25.0)	2 (15.4)	0.690
Best supportive care	4 (10.8)	1 (4.2)	3 (23.1)	0.120

¹There were 37/83 (44.6%) patients who had disease progression after atezolizumab plus bevacizumab therapy. EBRT: External beam radiotherapy; mALBI: Modified albumin-bilirubin; TACE: Transarterial chemoembolization.

Table 5 Predictors of overall survival in unresectable hepatocellular carcinoma patients who received atezolizumab plus bevacizumab therapy

Variables	Univariate		Multivariate
	Hazard ratio (95%CI)	P value	Adjusted hazard ratio (95%CI)	P value
Age	1.00 (0.97-1.02)	0.970	0.99 (0.96-1.02)	0.540
Male sex	1.15 (0.51-2.60)	0.740	0.97 (0.41-2.28)	0.940
ECOG-PS
0	1.00 (Reference)
1	2.03 (0.62-6.66)	0.240
Presence of cirrhosis
No	1.00 (Reference)
Yes	2.19 (0.53-9.13)	0.280
Etiology of disease
NASH	0.70 (0.32-1.52)	0.360
Viral hepatitis	1.48 (0.73-2.97)	0.280
Alcohol	2.09 (0.81-5.39)	0.130
BCLC stage
B	1.00 (Reference)
C	0.66 (0.33-1.31)	0.230
Extrahepatic metastasis
No	1.00 (Reference)
Yes	0.70 (0.37-1.32)	0.270
Portal invasion
No	1.00 (Reference)
Yes	1.29 (0.68-2.47)	0.440
AFP > 500 ng/mL	1.26 (0.67-2.36)	0.480
CTP class
A	1.00 (Reference)
B	5.38 (2.66-10.89)	< 0.001	2.63 (1.19-5.78)	0.020
mALBI grade
1 + 2a	1.00 (Reference)
2b + 3	5.20 (2.52-10.76)	< 0.001	3.90 (1.71-8.90)	0.001
Prior treatment for HCC
No	1.00 (Reference)
Yes	0.87 (0.42-1.78)	0.700
Prior local therapy for HCC
No	1.00 (Reference)
Yes	0.79 (0.39-1.58)	0.500
Prior systemic therapy for HCC
No	1.00 (Reference)
Yes	1.80 (0.79-4.11)	0.160
Combination of AB and local treatment as first-line treatment
No	1.00 (Reference)
Yes	0.05 (0.01-27.12)	0.340

AB: Atezolizumab plus bevacizumab; AFP: Alpha fetoprotein; BCLC: Barcelona Clinic Liver Cancer; CI: Confidence interval; CTP: Child-Turcotte-Pugh; ECOG-PS: Eastern Cooperative Oncology Group Performance Status; HCC: Hepatocellular carcinoma; mALBI: Modified albumin-bilirubin; NASH: Nonalcoholic steatohepatitis.