Cost-effectiveness analysis of seven treatments vs sorafenib as first-line therapy for advanced hepatocellular carcinoma in China

Table 1 Bayesian surface under the cumulative ranking curve and ranking profiles for efficacy endpoints (progression-free survival and overall survival)

Treatment	PFS			OS			Mean (PFS and OS)
	SUCRA (%)	Rank	PrBest (%)	SUCRA (%)	Rank	PrBest (%)	SUCRA (%)	Rank
Placebo	0	23	0	1	22.8	0	0.50	22.90
Sorafenib	28.2	16.8	0	28.5	16.7	0	28.35	16.75
Lenvatinib	75.5	6.4	0	43.5	13.4	0	59.50	9.90
Donafenib	38.4	14.6	0	59.1	10	0	48.75	12.30
Sintilimab plus IBI305	85.7	4.2	0	92.3	2.7	6.8	89.00	3.45
Rivoceranib plus camrelizumab	89.7	3.3	0.1	88.9	3.5	2.2	89.30	3.40
Tislelizumab	15.3	19.6	0	57.4	10.4	0	36.35	15.00
Avastin plus tecentriq	74	6.7	0	85.2	4.3	0.9	79.60	5.50
Cabozantinib plus atezolizumab	75.4	6.4	0	48.6	12.3	0	62.00	9.35
Single Tremelimumab Regular Interval Durvalumab	44.4	13.2	0	71	7.4	0	57.70	10.30
Durvalumab	25	17.5	0	55.5	10.8	0	40.25	14.15
Lenvatinib plus pembrolizumab	89.1	3.4	0	70.1	7.6	0	79.60	5.50
Lenvatinib plus TACE	100	1	99.9	99.4	1.1	89.9	99.70	1.05
Sorafenib plus TACE	63.4	9	0	45.6	13	0	54.50	11.00
Nivolumab	38.7	14.5	0	57.4	10.4	0	48.05	12.45
Sorafenib plus erlotinib	12.2	20.3	0	42.1	13.7	0	27.15	17.00
Linifanib	60.9	9.6	0	22.4	18.1	0	41.65	13.85
Sunitinib	12.1	20.3	0	4.9	21.9	0	8.50	21.10
Brivanib	26.8	17.1	0	19.2	18.8	0	23.00	17.95
Sorafenib plus pravastatin	28.5	16.7	0	31.3	16.1	0	29.90	16.40
Sorafenib plus doxorubicin	37.9	14.7	0	24.3	17.7	0	31.10	16.20
Sorafenib plus hepatic arterial infusion chemotherapy	60.2	9.8	0	31.4	16.1	0	45.80	12.95
Avastin plus toripalimab	68.6	7.9	0	70.9	7.4	0.1	69.75	7.65

OS: Overall survival; PFS: Progression-free survival; PrBest: Probability of being best; SUCRA: Surface under the cumulative ranking curve; TACE: Transarterial chemoembolization.

Table 2 Bayesian surface under the cumulative ranking curve and ranking profiles for safety endpoints (adverse events)

Treatment	AEs of any grade			Grade ≥ 3 AEs
	SUCRA (%)	Rank	PrBest (%)	SUCRA (%)	Rank	PrBest (%)
Placebo	96.5	1.5	48.3	77.8	5.0	0
Sorafenib	32.9	11.1	0	55.9	8.9	0
Lenvatinib	46.2	9.1	0	28	14	0
Donafenib	53.3	8.0	0	74.8	5.5	0
Sintilimab plus IBI305	20.7	12.9	0	31.5	13.3	0
Rivoceranib plus camrelizumab	4	15.4	0	4.4	18.2	0
Tislelizumab	80.7	3.9	0	93.9	2.1	16.1
Avastin plus tecentriq	68.5	5.7	0	55.9	8.9	0
Cabozantinib plus atezolizumab	11.1	14.3	0	13.3	16.6	0
Single Tremelimumab Regular Interval Durvalumab	70.9	5.4	0	78.4	4.9	0
Durvalumab	96.8	1.5	51.7	98.6	1.3	79.5
Lenvatinib plus pembrolizumab	37.5	10.4	0	16.9	16.0	0
Lenvatinib plus TACE	NA	NA	NA	NA	NA	NA
Sorafenib plus TACE	NA	NA	NA	3.2	18.4	0
Nivolumab	85.9	3.1	0	90.8	2.7	4.5
Sorafenib plus erlotinib	35.2	10.7	0	47.8	10.4	0
Linifanib	16.3	13.6	0	29.9	13.6	0
Sunitinib	NA	NA	NA	35.1	12.7	0
Brivanib	43.6	9.5	0	48.6	10.2	0
Sorafenib plus pravastatin	NA	NA	NA	NA	NA	NA
Sorafenib plus doxorubicin	NA	NA	NA	NA	NA	NA
Sorafenib plus hepatic arterial infusion chemotherapy	NA	NA	NA	NA	NA	NA
Avastin plus toripalimab	NA	NA	NA	65	7.3	NA

AEs: Adverse events; NA: Not available; PrBest: Probability of being best; SUCRA: Surface under the cumulative ranking curve; TACE: Transarterial chemoembolization.

Table 3 Model parameters

Model variables	Base line value (range)		Minimum	Maximum	Distribution	Source
Survival distribution
PFS of sorafenib	μ = -1.079, σ = 0.855		Fixed	Fixed	Log-normal	Model fitting
OS of sorafenib	μ = 0.115, σ = 0.992		Fixed	Fixed	Log-normal	Model fitting
PFS of lenvatinib	μ = -0.515, σ = 1.100		μ = -0.218, σ = 1.219	μ = -0.785, σ = 0.990	Log-normal	NMA
OS of lenvatinib	μ = 0.407, σ = 1.075		μ = 0.689, σ = 1.171	μ = 0.144, σ = 1.003	Log-normal	NMA
PFS of camrelizumab plus rivoceranib	μ = -0.582, σ = 1.043		μ = -0.339, σ = 1.135	μ = -0.791, σ = 0.961	Log-normal	NMA
OS of camrelizumab plus rivoceranib	μ = 0.534, σ = 1.129		μ = 811, σ = 1.207	μ = 0.256, σ = 1.044	Log-normal	NMA
PFS of sintilimab plus IBI305	μ = -0.592, σ = 1.016		μ = -0.376, σ = 1.093	μ = -0.782, σ = 0.947	Log-normal	NMA
OS of sintilimab plus IBI305	μ = 0.592, σ = 1.108		μ = 0.858, σ = 1.176	μ = 0.339, σ = 1.039	Log-normal	NMA
PFS of L + P	μ = -0.350, σ = 1.166		μ = 0.179, σ = 1.360	μ = -0.809, σ = 0.971	Log-normal	NMA
OS of L + P	μ = 0.692, σ = 1.157		μ = 1.240, σ = 1.311	μ = 0.205, σ = 1.042	Log-normal	NMA
PFS of atezolizumab plus bevacizumab	μ = -0.649, σ = 1.007		μ = -0.232, σ = 1.160	μ = -1.009, σ = 0.861	Log-normal	NMA
OS of atezolizumab plus bevacizumab	μ = 0.878, σ = 1.199		μ = 1.508, σ = 1.360	μ = 0.328, σ = 1.042	Log-normal	NMA
PFS of L + T	μ = 0.477, σ = 1.467		μ = 0.930, σ = 1.6380	μ = 0.023, σ = 1.3025	Log-normal	NMA
OS of L + T	μ = 1.267, σ = 1.337		μ = 1.771, σ = 1.483	μ = 0.824, σ = 1.228	Log-normal	NMA
Treatment cost ($)
Sorafenib; Bayer (per plate)	12.07		Fixed	Fixed	Gamma	Bid-winning price
Lenvatinib; Eisai (per plate)	15.17		12.14	18.2	Gamma	Bid-winning price
Sintilimab; Xinda (per cycle)	303.37		242.7	364.04	Gamma	Bid-winning price
IBI305; Xinda (per kg)	23.51		18.81	28.21	Gamma	Bid-winning price
Apatinib; Hengrui (per plate)	14.69		11.75	17.63	Gamma	Bid-winning price
Camrelizumab; Hengrui (per cycle)	361.89		289.51	434.27	Gamma	Bid-winning price
Atezolizumab; Roche (per cycle)	4606.74		3685.39	5528.09	Gamma	Bid-winning price
Bevacizumab; Roche (per 100 mg)	210.67		168.54	252.8	Gamma	Bid-winning price
Pembrolizumab; Merck (per cycle)	5033.15		4026.52	6039.78	Gamma	Bid-winning price
Regofenib, Bayer (per plate)	24.16		19.33	28.99	Gamma	Bid-winning price
TACE (per cycle)	2986.24		2388.99	3583.49	Gamma	Bid-winning price
Best supportive care (per year)	3180		2544	3816	Gamma
Bed charge (per cycle)	58.57		46.86	70.28	Gamma	Bid-winning price
Follow-up and monitoring (per year)	659.58		527.66	791.5	Gamma
Hospice care (per person)	1839		1471.2	2206.8	Gamma
Cost of adverse events ($)
Proteinuria	562.64		450.11	675.17	Gamma	DRG
Hypertension	520.51		416.41	624.61	Gamma	DRG
Asthenia	0		0	0	Gamma	DRG
Rash	245.79		196.63	294.95	Gamma	DRG
Hand-foot syndrome	245.79		196.63	294.95	Gamma	DRG
RCCEP	577.11		461.69	692.53	Gamma	DRG
Diarrhea	630.2		504.16	756.24	Gamma	DRG
Increased AST	474.72		379.78	569.66	Gamma	DRG
Increased blood bilirubin	439.75		351.8	527.7	Gamma	DRG
Neutropenia	586.8		469.44	704.16	Gamma	DRG
Decreased platelet count	582.02		465.62	698.42	Gamma	DRG
Anemia	685.67		548.54	822.8	Gamma	DRG
Sorafenib	174.72		139.78	209.66	Gamma	Calculation
Lenvatinib	234.41		187.53	281.29	Gamma	Calculation
Camrelizumab plus rivoceranib	505.2		404.16	606.24	Gamma	Calculation
Sintilimab plus IBI308	177.39		141.91	212.87	Gamma	Calculation
Atezolizumab plus bevacizumab	126.12		100.9	151.34	Gamma	Calculation
L + P	262.36		209.89	314.83	Gamma	Calculation
L + T	329.78		263.82	395.74	Gamma	Calculation
After progression	283.15		226.52	339.78	Gamma	Calculation
Other parameters
Weight	65		52	78	Normal
Discount rate	0.05		0	0.08	Uniform
Cycle of TACE	3		1	6	Uniform
Exchange rate	7.12		-	-	-	Fixed
Utility
PFS	0.76		0.608	0.912	Beta
Progressive disease	0.68		0.544	0.816	Beta
Disutiliy of toxicities
Proteinuria	0		0	0	Beta
Hypertension	0.08		0.064	0.096	Beta
Asthenia	0.1		0.08	0.12	Beta
Rash	0.1		0.08	0.12	Beta
Hand-foot syndrome	0.116		0.093	0.139	Beta
RCCEP	0.1		0.08	0.12	Beta
Diarrhea	0.05		0.04	0.06	Beta
Increased AST	0		0	0	Beta
Increased blood bilirubin	0		0	0	Beta
Neutropenia	0.2		0.16	0.24
Decreased platelet count	0.11		0.088	0.132	Beta
Anemia	0.07		0.056	0.084	Beta
Sorafenib	0.036		0.029	0.043	Beta	Calculation
Lenvatinib	0.034		0.027	0.041	Beta	Calculation
Camrelizumab plus rivoceranib	0.08		0.064	0.096	Beta	Calculation
Sintilimab plus IBI305	0.018		0.014	0.022	Beta	Calculation
Atezolizumab plus bevacizumab	0.01		0.008	0.012	Beta	Calculation
L + P	0.032		0.026	0.038	Beta	Calculation
L + T	0.031		0.0248	0.0372	Beta	Calculation
After progression	0.044		0.0352	0.0528	Beta	Calculation

AST: Aspartate aminotransferase; DRG: Diagnosis-Related Group; L + P: Lenvatinib plus pembrolizumab; L + T: Lenvatinib plus transarterial chemoembolization; NMA: Network meta-analysis; OS: Overall survival; PFS: Progression-free survival; RCCEP: Reactive cutaneous capillary endothelial proliferation; TACE: Transarterial chemoembolization.

Table 4 Base-case analysis results

Treatment	QALYs PFS	QALYs PD	QALYs total	Cost PFS ($)	Cost PD ($)	Cost total ($)	InCr cost ($)	InCr QALYs	Incremental cost-effectiveness ratio ($/QALY)	Acceptability at willingness-to-pay	Probability optimal
Sorafenib	0.35	0.72	1.07	10380.95	36112.17	46493.12	Reference	Reference	Reference	Reference	11.30%
Avastin plus toripalimab	0.5	0.89	1.39	31707.84	44091.81	75799.65	19276.99	0.32	91582.91	0.00%	0.00%
Lenvatinib	0.73	0.73	1.46	29365.81	36404.3	65770.11	18599.42	0.39	49428.18	48.50%	5.90%
Rivoceranib plus camrelizumab	0.61	0.96	1.57	18063.18	47029.36	65092.54	35766.97	0.5	37198.84	50.60%	14.90%
Sintilimab plus IBI305	0.64	1.04	1.68	31308.96	50951.13	82260.09	44502.34	0.61	58634.38	0.10%	0.00%
Lenvatinib plus pembrolizumab	0.88	0.97	1.85	43623.22	47372.24	90995.46	59589.61	0.78	57054.28	0.60%	0.00%
Avastin plus tecentriq	0.61	1.46	2.07	35119.31	70963.42	106082.73	63425.79	1	59589.61	0.00%	0.00%
Lenvatinib plus transarterial chemoembolization	1.9	0.85	2.75	68059.03	41859.88	109918.91	29306.53	1.68	37753.45	73.50%	67.90%

InCr: Increased; PD: Progressive disease state; PFS: Progression-free survival; QALY: Quality-adjusted life year.