Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Table 1 Efficacy results of the RESORCE phase III trial

Outcome based on assessment per mRECIST	Regorafenib n = 379 (%)	Placebo n = 194 (%)	HR (95%CI)	P value
Response
Complete	2 (1)	0	-	NR
Partial	38 (10)	8 (4)	-	NR
Overall response rate	40 (11)	8 (4)	-	0.0047
Stable disease	206 (54)	62 (32)	-	NR
Disease control rate	247 (65)	70 (36)	-	< 0.0001
Overall survival in mo
Median	10.6	7.8	0.63	< 0.0001
95%CI	9.1-12.1	6.3-8.8	(0.50-0.79)
Progression-free survival in mo
Median	3.1	1.5	0.46	< 0.0001
95%CI	2.8-4.2	1.4-1.6	(0.37-0.56)
Time to progression in mo
Median	3.2	1.5	0.44	< 0.0001
95%CI	(2.9-4.2)	(1.4-1.6)	(0.36-0.55)
Outcome based on assessment per RECIST 1.1
Response
Complete	0	0	-	NR
Partial	25 (7)	5 (3)	-	NR
Overall response rate	25 (7)	5 (3)	-	0.02
Stable disease	223 (59)	62 (32)	-	NR
Disease control rate	249 (66)	67 (35)	-	< 0.0001
Progression-free survival in mo
Median	3.4	1.5	0.43	< 0.0001
95%CI	2.9-4.2	1.4-1.5	(0.35-0.52)
Time to progression in mo
Median	3.9	1.5	0.41	< 0.0001
95%CI	(2.9-4.2)	(1.4-1.6)	(0.34-0.51)

Adapted from: Bruix et al[14]; Bruix et al[18]. CI: Confidence interval; NR: Not reported; HR: Hazard ratio.

Table 2 Adverse events in the RESORCE phase III trial occurring in ≥ 10% of patients–Safety population

	Adverse events, n (%)						Treatment-related adverse events, n (%)
	Regorafenib			Placebo			Regorafenib			Placebo
	n = 374			n = 193			n = 374			n = 193
	Any G	G 3	G 4	Any G	G 3	G 4	Any G	G 3	G 4	Any G	G 3	G 4
Any AE	374 (100)	208 (56)	40 (11)	179 (93)	61 (32)	14 (7)	346 (93)	173 (46)	14 (4)	100 (52)	31 (16)	1 (1)
HFSR	198 (53)	47 (13)	NA	15 (8)	1 (1)	NA	196 (52)	47 (13)	NA	13 (7)	1 (1)	NA
Diarrhea	155 (41)	12 (3)	0	29 (15)	0	NA	125 (33)	9 (2)	0	18 (9)	0	0
Fatigue	151 (40)	34 (9)	NA	61 (32)	9 (5)	NA	110 (29)	24 (6)	NA	37 (19)	3 (2)	NA
Hypertension	116 (31)	56 (15)	1 (< 1)	12 (6)	9 (5)	0	87 (23)	48 (13)	1 (< 1)	9 (5)	6 (3)	0
Anorexia	116 (31)	10 (3)	0	28 (15)	4 (2)	0	88 (24)	10 (3)	0	12 (6)	0	0
Increased bilirubin	108 (29)	37 (10)	2 (1)	34 (18)	15 (8)	6 (3)	70 (19)	24 (6)	1 (< 1)	7 (4)	4 (2)	0
Increased AST	92 (25)	37 (10)	4 (1)	38 (20)	19 (10)	3 (2)	48 (13)	16 (4)	3 (1)	15 (8)	9 (5)	1 (1)
Fever	72 (19)	0	0	14 (7)	0	0	14 (4)	0	0	4 (2)	0	0
Nausea	64 (17)	2 (1)	NA	26 (13)	0	NA	40 (11)	1 (< 1)	NA	13 (7)	0	NA
Increased ALT	55 (15)	10 (3)	2 (1)	22 (11)	5 (3)	0	29 (8)	6 (2)	2 (1)	8 (4)	2 (1)	0
Weight loss	51 (14)	7 (2)	NA	9 (5)	0	NA	27 (7)	4 (1)	NA	3 (2)	0	NA
Oral mucositis	47 (13)	4 (1)	0	6 (3)	1 (1)	0	42 (11)	4 (1)	0	5 (3)	1 (1)	0
Vomiting	47 (13)	3 (1)	0	13 (7)	1 (1)	0	27 (7)	1 (< 1)	0	5 (3)	0	0
Cough	40 (11)	1 (< 1)	NA	14 (7)	0	NA	4 (1)	0	NA	2 (1)	0	NA
Hypophosphatemia	37 (10)	30 (8)	2 (1)	4 (2)	3 (2)	0	22 (6)	16 (4)	2 (1)	2 (1)	1(1)	0
Hoarseness	39 (10)	0	NA	1 (1)	0	NA	34 (9)	0	NA	0	0	NA

Adapted from: Bruix et al[14]. G: Grade; AE: Adverse event; HFSR: Hand-foot skin reaction; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; NA: Not applicable.

Table 3 Efficacy results of the CELESTIAL phase III trial

Outcome	Cabozantinib	Placebo	HR	P value
Intent to treat population	n = 470 (%)	n = 237 (%)	(95%CI)
Overall response rate				0.009
Partial response	18 (4)	1 (< 1)	-
95%CI	(2.3-6.0)	(0.0-2.3)
Stable disease	282 (60)	78 (33)	-	NR
Disease control rate	300 (64)	79 (33)	-	NR
Overall survival in mo
Median	10.2	8.0	0.76	0.005
95%CI	9.1-12.0	6.8-9.4	(0.63-0.92)
Progression-free survival in mo
Median	5.2	1.9	0.44	< 0.001
95%CI	4.0-5.5	1.9-1.9	(0.36-0.52)
Time to progression in mo				NR
Median	5.4	1.9	0.41
95%CI	(4.0-5.6)	(1.9-1.9)	(0.34-0.49)
Patients who have only received sorafenib as prior therapy	n = 335 (%)	n = 174 (%)	HR (95%CI)	P value
Overall survival in mo
Median	11.3	7.2	0.70	NR
95%CI	9.5-13.9	5.8-9.3	(0.55-0.88)
Progression-free survival in mo
Median	5.5	1.9	0.40	NR
95%CI	4.6-5.7	1.9-1.9	(0.32-0.50)

Adapted from: Abou-Alfa et al[34]; Merle et al[35]; Kelley et al[36]. CI: Confidence interval; NR: Not reported; HR: Hazard ratio.

Table 4 Adverse events in the CELESTIAL phase III trial occurring in ≥ 10% of patients regardless of causality–Safety population

	Adverse events, n (%)
	Cabozantinib		Placebo
	n = 467		n = 237
	Any G	G 3-41	Any G	G 3-41
Any AE	460 (99)	316 (68)	219 (92)	86 (37)
Diarrhea	251 (54)	46 (10)	44 (19)	4 (2)
Decreased appetite	225 (48)	27 (6)	43 (18)	1 (< 1)
PPE	217 (46)	79 (17)	12 (5)	0
Fatigue	212 (45)	49 (10)	70 (30)	10 (4)
Nausea	147 (31)	10 (2)	42 (18)	4 (2)
Hypertension	137 (29)	74 (16)	14 (6)	4 (2)
Vomiting	121 (26)	2 (< 1)	28 (12)	6 (3)
Increased AST	105 (22)	55 (12)	27 (11)	16 (6)
Asthenia	102 (22)	32 (7)	18 (8)	4 (2)
Dysphonia	90 (19)	3 (1)	5 (2)	0
Constipation	87 (19)	2 (< 1)	45 (19)	0
Abdominal pain	83 (18)	8 (1)	60 (25)	10 (4)
Weight loss	81 (17)	5 (1)	14 (6)	0
Increased ALT	80 (17)	23 (5)	13 (5)	5 (2)
Mucosal inflammation	65 (14)	8 (2)	5 (2)	1 (< 1)
Fever	64 (14)	0	24 (10)	1 (< 1)
Upper abdominal pain	63 (13)	3 (1)	31 (13)	0
Cough	63 (13)	1 (< 1)	26 (11)	0
Peripheral edema	63 (13)	4 (1)	32 (14)	2 (1)
Stomatitis	63 (13)	8 (2)	5 (2)	0
Dyspnea	58 (12)	15 (3)	24 (10)	1 (< 1)
Rash	58 (12)	2 (< 1)	146 (6)	1 (< 1)
Ascites	57 (12)	18 (4)	30 (13)	11 (5)
Dysgeusia	56 (12)	0	5 (2)	0
Hypoalbuminemia	55 (12)	2 (< 1)	12 (5)	0
Headache	52 (11)	1 (< 1)	16 (7)	1 (< 1)
Thrombocytopenia	52 (11)	16 (3)	1 (< 1)	0

¹Mostly grade 3; Adapted from: Abou-Alfa et al[34]. G: Grade; AE: Adverse event; PPE: Palmar-plantar erythrodysesthesia; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Table 5 Efficacy results of the REACH-2 phase III trial

Outcome	Ramucirumab n = 197 (%)	Placebo n = 95 (%)	HR (95%CI)	P value
Response
Complete	0	0	-	NR
Partial	9 (4.6)	1 (1.1)	-	NR
Overall response rate	9 (4.6)	1 (1.1)	-	0.1697
Stable disease	109 (55.3)	36 (37.9)	-	NR
Disease control rate	118 (59.9)	37 (38.9)	-	0.0006
Overall survival in mo			0.71 (0.53–0.94)	0.0199
Median	8.5	7.3
95%CI	7.0-10.6	5.4-9.1
Progression-free survival in mo			0.45 (0.33–0.60)	< 0.0001
Median	2.8	1.6
95%CI	2.8–4.1	1.5–2.7
Time to progression in mo			0.42 (0.31–0.58)	< 0.0001
Median	3.0	1.6
95%CI	(2.8–4.2)	(1.5–2.7)

Adapted from: Zhu et al[57]. CI: Confidence interval; NR: Not reported; HR: Hazard ratio.

Table 6 Adverse events in the REACH-2 phase III trial occurring in ≥ 10% of patients–Safety population

	Adverse events, n (%)						Treatment-related adverse events, n (%)
	Ramucirumab			Placebo			Ramucirumab			Placebo
	n = 197			n = 95			n = 197			n = 95
	Any G	G 3	G 4	Any G	G 3	G 4	Any G	G 3	G 4	Any G	G3	G 4
Fatigue	54 (27)	7 (4)	NA	16 (17)	3 (3)	NA	28 (14)	2 (1)	NA	5 (5)	0	NA
Peripheral edema	50 (25)	3 (2)	0	13 (14)	0	0	15 (8)	2 (1)	0	5 (5)	0	0
Decreased appetite	46 (23)	3 (2)	0	19 (20)	1 (1)	0	21 (11)	0	NA	4 (4)	0	0
Abdominal pain	39 (20)	3 (2)	NA	12 (13)	2 (2)	NA	8 (4)	1 (1)	1 (< 1)	3 (3)	0	NA
Nausea	37 (19)	0	NA	11 (12)	0	NA	23 (12)	0	0	2 (2)	0	NA
Diarrhea	32 (16)	0	0	13 (14)	1 (1)	0	14 (7)	0	1 (< 1)	5 (5)	1 (1)	0
Headache	28 (14)	0	NA	5 (5)	1 (1)	NA	12 (6)	0	3 (1)	0	0	NA
Constipation	27 (14)	1 (1)	0	19 (20)	1 (1)	0	3 (2)	1 (1)	0	3 (3)	0	0
Insomnia	21 (11)	0	NA	6 (6)	1 (1)	NA	1 (1)	0	NA	0	0	NA
Pyrexia	20 (10)	0	0	3 (3)	0	0	4 (2)	0	2 (1)	1 (1)	0	0
Vomiting	20 (10)	0	0	7 (7)	0	0	5 (3)	0	NA	1 (1)	0	0
Bleeding or hemorrhage events	48 (24)	9 (5)	1 (1)	12 (13)	2 (2)	1 (1)	21 (11)	1 (< 1)	0	5 (5)	0	1 (1)
Epistaxis	27 (14)	1 (1)	0	3 (3)	0	0	14 (7)	0	0	2 (2)	0	0
GI hemorrhage events	12 (6)	7 (4)	0	5 (5)	2 (2)	0	1 (1)	1 (1)	0	0	0	0
Hepatic hemorrhage events	1 (1)	0	1 (1)	0	0	0	0	0	0	0	0	0
Pulmonary hemorrhage events	5 (2)	1 (1)	0	0	0	0	0	0	0	0	0	0
Hypertension	49 (25)	25 (13)	0	12 (13)	5 (5)	0	32 (16)	15 (8)	0	6 (6)	2 (2)	0
Proteinuria	40 (20)	4 (2)	0	4 (4)	0	0	27 (14)	4 (2)	0	3 (3)	0	0
Arterial TE events	5 (3)	0	1 (1)	1 (1)	0	0	4 (2)	0	1 (1)	0	0	0
Venous TE events	2 (1)	0	0	2 (2)	1 (1)	0	1 (1)	0	0	1 (1)	0	0
GI perforation	2 (1)	2 (1)	0	2 (2)	2 (2)	0	1 (1)	1 (1)	0	0	0	0
Congestive heart failure	1 (1)	0	0	1 (1)	1 (1)	0	0	0	0	0	0	0
Fistula	1 (1)	0	0	0	0	0	0	0	0	0	0	0
Liver injury or failure	78 (40)	28 (14)	4 (2)	28 (29)	14 (15)	1 (1)	17 (9)	3 (2)	0	2 (2)	0	0
Ascites	35 (18)	7 (4)	0	7 (7)	2 (2)	0	4 (2)	1 (1)	0	1 (1)	0	0
Hepatic encephalopathy	8 (4)	5 (3)	1 (1)	0	0	0	2 (1)	1 (1)	0	0	0	0
Infusion related reactions	17 (9)	28 (14)	0	3 (3)	0	0	13 (7)	0	0	2 (2)	0	0

Adapted from: Zhu et al[57]. G: Grade; AE: Adverse event; NA: Not applicable; GI: Gastrointestinal; TE: Thromboembolic.