First-Line Treatment for Advanced Hepatocellular Carcinoma: A Three-Armed Real-World Comparison

Figures & data

Table 1 Baseline Parameters

Variable	All (n=177)	Sorafenib (n=118)	Lenvatinib (n=21)	Atez/Bev (n=38)	Global p-value	p-value Sorafenib vs Atez/Bev	p-value Lenvatinib vs Atez/Bev
Age	66 (58–73)	66 (58–72)	67 (61–73)	68 (59–74)	0.679
Male	136 (76.8%)	94 (79.7%)	12 (57.1%)	30 (78.9%)	0.075
BMI	26 (23–30)	26 (23–29)	26 (24–30)	27 (24–30)	0.985
Weight	81 (72–95)	80 (74–95)	75 (72–100)	84 (71–95)	0.641
ECOG					0.510
0/1	133 (75.1%)	82 (69.5%)	17 (80.9%)	34 (89.5%)
≥2	44 (24.9%)	36 (30.5%)	4 (19.0%)	4 (10.5%)
Child-Pugh-Class					0.028	0.025	1.000
A	109 (61.6%)	63 (53.4%)	16 (76.2%)	30 (78.9%)
B/C	60 (33.9%)	47 (39.8%)	5 (23.8%)	8 (21.1%)
Unknown	8 (4.5%)	8 (6.8%)	0	0
Etiology
Presence of Cirrhosis	150 (84.8%)	104 (88.1%)	18 (85.7%)	28 (73.7%)	0.099
Alcohol	42 (23.7%)	29 (24.6%)	9 (42.9%)	4 (10.5%)	0.019	0.096	0.012
HBV	30 (17.0%)	19 (16.1%)	2 (9.5%)	9 (23.7%)	0.351
HCV	47 (26.6%)	37 (31.4%)	3 (14.3%)	7 (18.4%)	0.118
NASH	31 (17.5%)	11 (9.3%)	9 (42.9%)	11 (29.0%)	0.000	0.009	0.426
Other	38 (21.5%)	30 (25.4%)	3 (14.3%)	5 (13.2%)	0.194
BCLC					0.000	0.002	<0.001
B	38 (21.5%)	21 (17.8%)	0	17 (44.7%)
C	138 (78.0%)	96 (81.4%)	21 (100.0%)	21 (55.3%)
D	1 (0.6%)	1 (0.8%)	0	0
Macrovascular invasion of main vessel	51 (28.8%)	28 (23.7%)	10 (47.6%)	13 (34.2%)	0.359
Extrahepatic Metastases	91 (51.4%)	62 (52.5%)	15 (71.4%)	14 (36.8%)	0.041	0.092	0.022
Maximal size of intrahepatic tumor. cm	6 (3–9)	6 (4–9)	6 (4–8)	5 (3–8)	0.629
Grading					0.299
1	14 (7.9%)	11 (9.3%)	0	3 (7.9%)
2	67 (37.8%)	42 (35.6%)	10 (47.6%)	15 (39.5%)
3	21 (11.9%)	12 (10.2%)	4 (19.0%)	5 (13.2%)
MELD-Score	8 (7–11)	9 (7–12)	7 (6–8)	8 (8–10)	0.010	0.267	0.030
ALBI-Score					0.007	0.009	1.000
1	49 (27.7%)	24 (20.3%)	8 (38.1%)	17 (44.7%)
2	84 (47.5%)	57 (48.3%)	11 (52.4%)	16 (42.1%)
3	33 (18.6%)	27 (22.9%)	1 (4.8%)	5 (13.2%)
Crafity-Score					0.027	0.017	0.027
0	69 (39.0%)	39 (33.1%)	7 (33.3%)	23 (60.5%)
1	73 (41.2%)	49 (41.5%)	14 (66.7%)	10 (26.3%)
2	5 (2.8%)	4 (3.4%)	0	1 (2.6%)
AFP-values	84 (10–1980)	173 (12–2389)	140 (13–5061)	26 (6–402)	0.173
AFP >400ng/mL	69 (40.8%)	50 (44.2%)	10 (47.6%)	9 (25.7%)	0.121
Previous therapies
Surgery	52 (29.4%)	32 (27.1%)	10 (47.6%)	10 (26.3%)	0.149
RFA/MWA/HIFU	14 (7.9%)	5 (4.2%)	2 (9.5%)	7 (18.4%)	0.019	0.019	0.611
SIRT	39 (22.0%)	23 (19.5%)	1 (4.8%)	15 (39.5%)	0.005	0.026	0.006
TACE	68 (38.4%)	45 (38.1%)	11 (52.4%)	12 (31.6%)	0.291
Transplantation	4 (2.3%)	3 (2.5%)	1 (4.8%)	0	0.471
TIPS	13 (7.3%)	10 (8.5%)	1 (4.8%)	2 (5.3%)	0.717
Treated varices at baseline	71 (40.1%)	52 (44.1%)	5 (23.8%)	14 (36.8%)	0.198
Second Line Therapy
Systemic Second-Line	48 (27.1%)	26 (22.0%)	12 (57.1%)	10 (26.3%)	<0.001	0.001	0.627

Notes: Numerical data are presented as median with range in parenthesis. Categorial data are presented as absolute frequency with relative frequency in parenthesis.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B; HCV, hepatitis C; NASH, non-alcoholic steatohepatitis; BCLC, Barcelona Clinic Liver Cancer; RFA, Radiofrequency Ablation; MWA, microwave ablation; HIFU, high-intensity focused ultrasound; SIRT, selective internal radiation therapy; TACE, transarterial chemoembolization; TIPS: transjugular intrahepatic portosystemic shunt.

Table 2 Response Rates

Response	Sorafenib Group	Lenvatinib Group	Atez/Bev Group	Global p-value	p-value Sorafenib vs Atez/Bev	p-value Lenvatinib vs Atez/Bev
Complete response	0	0	1 (2.6%)	<0.001	0.077	0.453
Partial response	5 (4.2%)	6 (28.6%)	11 (28.9%)	<0.001	<0.001	0.976
Stable disease	18 (15.3%)	3 (14.3%)	9 (23.7%)	<0.001	0.232	0.391
Progressive disease	79 (66.9%)	9 (42.9%)	17 (44.7%)	<0.001	0.014	0.889
Objective response rate	5 (4.2%)	6 (28.6%)	12 (31.6%)	<0.001	<0.001	0.870
Disease control rate	23 (19.5%)	9 (42.9%)	21 (55.3%)	<0.001	<0.001	0.779

Note: Data are presented as absolute frequency with relative frequency in parenthesis.

Figure 1 “Overall and progression free survival” (A) Kaplan-Meier graph of overall survival: p=0.088 (Log rank test) (B) Kaplan-Meier graph of progression free survival: p=0.075 (Log rank test). Global p-values are shown. Tick marks indicate censored data.

Figure 2 Progression free survival for different subgroups (A) CHILD A; (B) CHILD B; (C) ALBI 1; (D) ALBI 2/3; (E) Alc, Alcohol; (F) NASH, non-alcoholic steatohepatitis; (G) HepB, hepatitis B; (H) HepC, hepatitis C; (I) TACE, transarterial chemoembolization; (J) SIRT, selective internal radiation therapy; (A-J, each Log rank test, CI: confidence interval) p-values and hazard ratios are for direct comparison to Atez/Bev.

Figure 3 Hazard ratios of individual parameters regarding PFS prediction depicted with 95% confidence intervals after using the Cox-proportional hazards model. Values >1 indicate a bad influence on PFS with higher grade of the parameter. Exception are the thrombocytes with lower values increasing the hazard ratio. Age is grouped in 10-year steps for better representability. Main vessel means macroscopic main vessel infiltration. (Cox Regression).

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group.

Table 3 Frequency of Adverse Events

Adverse Events	Sorafenib		Lenvatinib		Atez/Bev
	(N=118)		(N=21)		(N=38)
	Grade ≥3	Any Grade	Grade ≥3	Any Grade	Grade ≥3	Any Grade
	Number (Percent)
Pulmonary embolism	0	0	2 (9.5%)	2 (9.5%)	0	0
Hypertension	3 (2.5%)	3 (2.5%)	0	6 (28.6%)	0	2 (5.3%)
Fatigue	22 (18.6%)	26 (22%)	1 (4.8%)	11 (52.4%)	0	1 (2.6%)
Dyspnea	11 (9.3%)	11 (9.3%)	0	1 (4.8%)	0	1 (2.6%)
Rash/Pruritus	10 (8.5%)	10 (8.5%)	0	1 (4.8%)	0	1 (2.6%)
Mucositis	5 (4.2%)	5 (4.2%)	1 (4.8%)	4 (19%)	0	0
Colitis	0	0	0	0	2 (5.3%)	2 (5.3%)
Cardiotoxicity	1 (0.8%)	1 (0.8%)	0	1 (4.8%)	1 (2.6%)	1 (2.6%)
Diarrhea	12 (10.2%)	15 (12.7%)	1 (4.8%)	4 (19%)	0	0
Anemia	9 (7.6%)	9 (7.6%)	0	0	0	5 (13.2%)
Hand-Feet-Syndrome	13 (11%)	14 (11.9%)	0	0	0	0
INR elevation	0	0	1 (4.8%)	1 (4.8%)	0	0
Nausea/Emesis	21 (17.8%)	24 (20.3%)	0	2 (9.5%)	2 (5.3%)	2 (5.3%)
irAE	0	0	0	0	2 (5.3%)	2 (5.3%)
Weight/appetite loss	6 (5.1%)	8 (6.8%)	0	7 (33.3%)	0	0
Proteinuria	0	0	0	2 (9.5%)	1 (2.6%)	1 (2.6%)
GIT-Bleeding	3 (2.5%)	3 (2.5%)	0	1 (4.8%)	1 (2.6%)	1 (2.6%)
Nosebleeds	1 (0.8%)	1 (0.8%)	0	0	0	0
Keratosis	1 (0.8%)	1 (0.8%)	0	0	0	0

Notes: We summarized urinary tract infections, pneumonias, fever and all other infections as infections; encephalopathia, dizziness, tremor, epileptic attacks and paresthesias as neurological AEs (Data are presented as absolute frequency with relative frequency in parenthesis.).

Abbreviations: Ire AE, Immune related adverse events; GIT-Bleeding, gastrointestinal bleeding.