Transarterial Chemoembolization Combined with Atezolizumab Plus Bevacizumab or Lenvatinib for Unresectable Hepatocellular Carcinoma: A Propensity Score Matched Study

Figures & data

Table 1 Baseline Characteristics of Patients Before Propensity Score Matching

Characteristics	Total (N = 98)	Atezo/Bev-TACE Group (n = 38)	LEN-TACE Group (n = 60)	P value
Age, years, median (IQR)	55.0 (47.0–63.3)	54.5 (41.8–61.3)	55.0 (49.3–66.0)	0.195
Gender, n (%)
Male	88 (89.8)	32 (84.2)	56 (93.3)	0.266
Female	10 (10.2)	6 (15.8)	4 (6.7)
ECOG performance status, n (%)
0	68 (69.4)	24 (63.2)	44 (73.3)	0.287
1	30 (30.6)	14 (36.8)	16 (26.7)
Etiology, n (%)
Hepatitis B	87 (88.8)	35 (92)	52 (86.7)	0.615
Other	11 (11.2)	3 (7.9)	8 (13.3)
No. of nodules, n (%)
1	23 (23.5)	5 (13.2)	18 (30.0)	0.153
2	17 (17.3)	8 (21.1)	9 (15.0)
≥3	58 (59.2)	25 (65.8)	33 (55.0)
BCLC stage, n (%)
B	19 (19.4)	5 (13.2)	14 (23.3)	0.214
C	79 (80.6)	33 (86.8)	46 (76.7)
Portal vein tumor thrombus, n (%)
Absent	39 (39.8)	11 (28.9)	28 (46.7)	0.116
Vp-1 and 2	23 (23.5)	13 (34.2)	10 (16.7)
Vp-3	14 (14.3)	4 (10.5)	10 (16.7)
Vp-4	22 (22.4)	10 (26.3)	12 (20.0)
Largest nodule, mean ± SE	96.1±41.3	95.3±44.4	96.7±39.6	0.868
Child–Pugh class, n (%)
A5	68 (69.4)	28 (73.7)	40 (66.7)	0.463
A6	30 (30.6)	10 (26.3)	20 (33.3)
ALBI grade, n (%)
1	43 (43.9)	20 (52.6)	23 (38.3)	0.165
2	55 (56.1)	18 (47.4)	37 (61.7)
Extrahepatic spread, n (%)
Absent	78 (79.6)	30 (78.9)	48 (80.0)	0.869
Present	20 (20.4)	8 (21.1)	12 (20.0)
Lung	6 (6.1)	3 (7.9)	3 (5.0)
Lymph nodes	7 (7.1)	3 (7.9)	4 (6.7)
Other	7 (7.1)	2 (5.3)	5 (8.3)
Time between first TACE and initiation of systemic therapy, days, median (IQR)	5.0 (3.0–8.0)	5.0 (2.0–8.0)	5.0 (3.0–8.8)	0.431
AFP, n (%)
≤400 ng/mL	50 (51.0)	17 (44.7)	33 (55.0)	0.322
>400 ng/mL	48 (49.0)	21 (55.3)	27 (45.0)
TBIL, μmol/mL, median (IQR)	11.8 (9.3–16.4)	11 (8.2–16.7)	12.1 (9.5–16.3)	0.574
AST, U/L, median (IQR)	47,5 (34.8–73.3)	54.5 (30.0–82.5)	46.0 (35.0–68.0)	0.623
ALT, U/L, median (IQR)	36.0 (25.0–53.5)	36.5 (21.8–50.8)	34.0 (26.0–56.0)	0.630
Albumin, g/L, mean ± SE	38.1±4.1	38.6±4.1	37.8±4.1	0.337
WBC, ×10^9/L, mean ± SE	6.1±2.0	6.1±1.8	6.1±2.2	0.985
Platelet, ×10^9/L, mean ± SE	208.3±96.6	213.9±97.5	204.8±96.8	0.653
PT, seconds, mean ± SE	13.8±1.0	13.9±0.8	13.8±1.1	0.686
INR, median (IQR)	1.05 (0.99–1.12)	1.05 (1.01–1.12)	1.04 (0.99–1.13)	0.743
Creatinine, umol/L, median (IQR)	71.0 (60.8–81.3)	70 (62.8–81.0)	71.0 (60.0–84.0)	0.748

Abbreviations: ECOG, Eastern Cooperative Oncology Group; AFP, alpha-fetoprotein; TBIL, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; WBC, white blood cell; INR, international normalized ratio; BCLC, Barcelona Clinic Liver Cancer; IQR, interquartile range; TACE, transarterial chemoembolization; Atezo/Bev, Atezolizumab plus Bevacizumab; LEN, lenvatinib.

Table 2 Baseline Characteristics of Patients After Propensity Score Matching

Characteristics	Total (N =68)	Atezo/Bev-TACE Group (n = 34)	LEN-TACE Group (n = 34)	P value
Age, years, median (IQR)	55.0 (47.0–63.8)	55.0 (42.0–62.0)	55.0 (48.8–66.0)	0.449
Gender, n (%)
Male	59 (86.8)	29 (85.3)	30 (88.2)	1.000
Female	9 (13.2)	5 (14.7)	4 (11.8)
ECOG performance status, n (%)
0	49 (72.1)	23 (67.6)	26 (76.5)	0.417
1	19 (27.9)	11 (32.4)	8 (23.5)
Etiology, n (%)
Hepatitis B	62 (91.2)	31 (91.2)	31 (91.2)	1.000
Other	3 (8.8)	3 (8.8)	3 (8.8)
No. of nodules, n (%)
1	14 (20.6)	5 (14.7)	9 (26.5)	0.401
2	13 (19.1)	6 (17.6)	7 (20.6)
≥3	41 (60.3)	23 (67.6)	18 (52.9)
BCLC stage, n (%)
B	14 (20.6)	5 (14.7)	9 (26.5)	0.230
C	54 (79.4)	29 (85.3)	25 (73.5)
Portal vein tumor thrombus, n (%)
Absent	22 (32.4)	11 (32.4)	11 (32.4)	0.344
Vp-1 and 2	19 (27.9)	10 (29.4)	9 (26.5)
Vp-3	11 (16.2)	3 (8.8)	8 (23.5)
Vp-4	16 (23.5)	10 (29.4)	6 (17.6)
Largest nodule, mean ± SE	97.9±42.3	96.5±46.0	99.4±38.8	0.787
Child–Pugh class, n (%)
A5	51 (75.0)	24 (70.6)	27 (79.4)	0.401
A6	17 (25.0)	10 (29.4)	7 (20.6)
ALBI grade, n (%)
1	36 (52.9)	17 (50.0)	19 (55.9)	0.627
2	32 (47.1)	17 (50.0)	15 (44.1)
Extrahepatic spread, n (%)
Absent	55 (80.9)	26 (76.5)	29 (85.3)	0.774
Present	13 (19.1)	8 (23.5)	5 (14.7)
Lung	5 (7.4)	3 (8.8)	2 (5.9)
Lymph nodes	4 (5.9)	3 (8.8)	1 (2.9)
Other	4 (5.9)	2 (5.9)	2 (5.9)
Time between first TACE and initiation of systemic therapy, days, median (IQR)	5.0 (3.0–8.8)	5.0 (2.0–8.3)	5.5 (3.0–9.0)	0.395
AFP, n (%)
≤400 ng/mL	32 (47.1)	16 (47.1)	16 (47.1)	1.000
>400 ng/mL	36 (52.9)	18 (52.9)	18 (52.9)
TBIL, μmol/mL, median (IQR)	12.1 (9.3–16.5)	11.0 (8.2–16.7)	12.7 (9.8–16.6)	0.620
AST, U/L, median (IQR)	47.0 (32.5–72.3)	54.5 (30.0–78.8)	42.0 (34.8–68.3)	0.169
ALT, U/L, median (IQR)	36.0 (24.3–53.0)	35.5 (21.8–48.5)	36.5 (26.0–56.0)	0.791
Albumin, g/L, mean ± SE	38.7±4.0	38.4±4.2	39.1±3.8	0.514
WBC, ×10^9/L, mean ± SE	6.0±1.9	5.9±1.8	6.0±2.0	0.935
Platelet, ×10^9/L, mean ± SE	203.3±92.3	203.6±91.2	203.0±94.7	0.979
PT, seconds, mean ± SE	13.8±1.0	13.9±0.8	13.7±1.3	0.283
INR, median (IQR)	1.04 (0.99–1.09)	1.05 (1.01–1.12)	1.03 (0.99–1.07)	0.062
Creatinine, umol/L, median (IQR)	70.5 (59.9–80.0)	70.0 (63.0–81.0)	71.0 (57.8–79.5)	0.668

Abbreviations: ECOG, Eastern Cooperative Oncology Group; AFP, alpha-fetoprotein; TBIL, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; WBC, white blood cell; INR, international normalized ratio; BCLC, Barcelona Clinic Liver Cancer; IQR, interquartile range; TACE, transarterial chemoembolization; Atezo/Bev, Atezolizumab plus Bevacizumab; LEN, lenvatinib.

Figure 1 Flowchart of the study.

Figure 2 Kaplan–Meier curves showing OS (A), PFS (B) and DOR (C) of each group.

Abbreviations: OS, overall survival; PFS, progression-free survival; DOR, duration of response; TACE, transarterial chemoembolization; Atezo/Bev, Atezolizumab plus Bevacizumab; LEN, lenvatinib.

Table 3 Summary of Best Overall Response

	RECIST 1.1			mRECIST
Best Response	Atezo/Bev-TACE (n=34)	LEN-TACE (n=34)	P value	Atezo/Bev-TACE (n=34)	LEN-TACE (n=34)	P value
Complete response (CR)	0 (0)	0 (0)		4 (11.8)	4 (11.8)
Partial response (PR)	9 (26.5)	5 (14.7)		17 (50.0)	16 (47.1)
Stable disease (SD)	17 (50.0)	24 (70.6)		7 (20.6)	9 (26.5)
Progressive disease (PD)	8 (23.5)	5 (14.7)		6 (17.6)	5 (14.7)
ORR (CR+PR)	9 (26.5)	5 (14.7)	0.230	21 (61.8)	20 (58.8)	0.804
DCR (CR+PR+SD)	26 (76.5)	29 (85.3)	0.355	28 (82.4)	29 (85.3)	0.742

Abbreviations: ORR, objective response rate; DCR, disease control rate; TACE, transarterial chemoembolization; Atezo/Bev, Atezolizumab plus Bevacizumab; LEN, lenvatinib.

Figure 3 Changes in sum of diameter of target lesions according to mRECIST criteria.

Figure 4 Forest plots with subgroup analysis for factors associated with (a) PFS and (b) OS.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; PVTT, Portal vein tumor thrombus; AFP, alpha-fetoprotein; TACE, transarterial chemoembolization; Atezo/Bev, Atezolizumab plus Bevacizumab; LEN, lenvatinib.

Table 4 Safety Profiles and Adverse Events

	Any Grade			Grades 3–4
	Group, No. (%)			Group, No. (%)
Adverse Event	Atezo/Bev-TACE Group (n=34)	LEN-TACE Group (n=34)	P value	Atezo/Bev-TACE Group (n=34)	LEN-TACE Group (n=34)	P value
Fever	14 (41.2)	17 (50.0)	0.465	0 (0)	0 (0)	1.000
Vomiting	15 (44.1)	18 (52.9)	0.467	0 (0)	0 (0)	1.000
Abdominal pain	20 (58.8)	17 (50.0)	0.465	4 (11.8)	3 (8.8)	1.000
Diarrhea	7 (20.6)	11 (32.4)	0.272	0 (0)	0 (0)	1.000
Constipation	10 (29.4)	13 (38.2)	0.442	1 (2.9)	0 (0)	1.000
Ascites	3 (8.8)	3 (8.8)	1.000	0 (0)	1 (2.9)	1.000
Thrombocytopenia	7 (20.6)	10 (29.4)	0.401	0 (0)	1 (2.9)	1.000
Anemia	14 (41.2)	11 (32.4)	0.451	0 (0)	3 (8.8)	0.239
Elevated AST	28 (82.4)	19 (55.9)	0.018	6 (17.6)	4 (11.8)	0.493
Elevated ALT	21 (61.8)	17 (50.0)	0.329	6 (17.6)	3 (8.8)	0.476
Hyperbilirubinemia	11 (32.4)	7 (20.6)	0.272	2 (5.9)	2 (5.9)	1.000
Hypoalbuminemia	6 (17.6)	4 (11.8)	0.493	0 (0)	0 (0)	1.000
Proteinuria	1 (2.9)	6 (17.6)	0.046	0 (0)	1 (2.9)	1.000
Hypertension	10 (29.4)	9 (26.5)	0.787	5 (14.7)	3 (8.8)	0.709
Hand-foot skin reaction	2 (5.9)	12 (35.3)	0.003	0 (0)	2 (5.9)	0.493
Gastrointestinal bleeding	4 (11.8)	6 (17.6)	0.493	1 (2.9)	2 (5.9)	1.000

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; TACE, transarterial chemoembolization; Atezo/Bev, Atezolizumab plus Bevacizumab; LEN, lenvatinib.