Systemic Therapy in Advanced Hepatocellular Carcinoma: Patient Selection and Key Considerations

Figures & data

Table 1 Selected phase III clinical studies with systemic treatment for hepatocellular carcinoma

	NCT	Study arm	Control arm	Patient numbers	Primary end point(s)	mOS (months)	HR	95% CI	p	FDA approval
First-line
SHARP^Citation6	00105443	Sorafenib	Placebo	602	OS, time to symptomatic progression	10.7 vs 7.9	0.69	0.55–0.87	<0.001	Yes
Asia-Pacific^Citation10	00492752	Sorafenib	Placebo	226	Not predefined	6.5 vs 4.2	0.68	0.50–0.93	0.014	NA
REFLECT^Citation11	01761266	Lenvatinib	Sorafenib	954	OS	13.6 vs 12.3	0.92	0.79–1.06	NA	Yes
NA^Citation12	02645981	Donafenib	Sorafenib	668	OS	12.1 vs 10.3	0.831	0.699–0.988	0.0245	NA
CheckMate 459^Citation13	02576509	Nivolumab	Sorafenib	743	OS	16.4 vs 14.7	0.85	0.71–1.02	0.075	No^b
IMbrave 150^Citation14–16	03434379	Atezolizumab–bevacizumab	Sorafenib	501	OS and PFS	19.2 vs 13.4	0.66	0.52–0.85	<0.001	Yes
Cosmic 312^Citation17	03755791	Atezolizumab–cabozantinib	Sorafenib	837	OS and PFS	15.4 vs 15.5	0.90	0.69–1.18^a	0.44	No
Orient-32^Citation18	03794440	Sintilimab–IBI305	Sorafenib	595^c	OS and PFS	Not reached vs 10.4	0.57	0.43–0.75	<0.0001	NA
HIMALAYA^Citation19	03298451	Tremelimumab–durvalumab	Sorafenib	1171	OS	16.43 vs 13.77	0.78	0.65–0.93	0.0035	Yes
NA^Citation20	03764293	Camrelizumab– apatinib	Sorafenib	543	OS and PFS	22.1 vs 15.2	0.62	0.49–0.80	<0.0001	No
RATIONALE 301^Citation21	03412773	Tislelizumab	Sorafenib	674	OS	15.9 vs 14.1	0.85	0.71–1.02	NA	No
Second-line
Resorce^Citation22	01774344	Regorafenib	Placebo	573	OS	10.6 vs 7.8	0.63	0.50–0.79	<0.0001^d	Yes
Celestial^Citation23	01908426	Cabozantinib	Placebo	707	OS	10.2 vs 8.0	0.76	0.63–0.92	0.005	Yes
Reach-2^Citation24	02435433	Ramucirumab	Placebo	292	OS	8.5 vs 7.3	0.71	0.531–0.949	0.0199	Yes
Keynote 240^Citation25	02702401	Pembrolizumab	Placebo	413	OS and PFS	13.9 vs 10.6	0.781	0.611–0.998	0.0238	Yes
Keynote 394^Citation26	03062358	Pembrolizumab	Placebo	453	OS	14.6 vs 13.0	0.79	0.63–0.99	0.0180	NA

Notes: ^a96.02% CI was reported in this study. ^bWas approved as second-line treatment, but voluntarily withdrawn after the negative phase III study. ^cIncluded 24 patients in the phase II safety run-in. ^dOne-sided.

Abbreviations: NCT, National Clinical Trial; mOS, median overall survival; NA, not applicable; PFS, progression-free survival.

Figure 1 Proposed treatment algorithm for advanced HCC patients who are eligible for systemic treatment.

Notes: *This regimen was FDA-approved recently. **Only for patients who do not have contraindications for immunotherapy, but have not received immunotherapy in first-line setting. Alternative options that may be considered in the future include camrelizumab–apatinib and tislelizumab, with recent studies demonstrating survival benefit and noninferiority compared to sorafenib, respectively.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; AFP, α-fetoprotein.

Table 2 Targets in hepatocellular carcinoma by different treatments

	VEGF	PD1/PDL1	CTLA4	RAF	PDGFR/c-Kit	FGFR	RET	Met	AXL/FLT3/TRKB	TIE2
Bevacizumab^Citation56	X
Apatinib^Citation57	X
Ramucirumab^Citation58,Citation59	X
Atezolizumab^Citation14		X
Pembrolizumab^Citation25		X
Durvalumab^Citation19		X
Camrelizumab^Citation60		X
Tislelizumab		X
Nivolumab^Citation61		X
Sintilimab^Citation62		X
Ipilimumab^Citation63			X
Tremelimumab^Citation19			X
Sorafenib^Citation6	X			X	X
Lenvatinib^Citation11	X				X	X	X
Donafenib^Citation12	X			X	X
Regorafenib^Citation22	X			X	X	X	X			X
Cabozantinib^Citation17	X						X	X	X	X

Abbreviations: VEGF, vascular endothelial growth factor; PD-1/PD-L1, programmed death protein-1/programmed death protein-Ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein-4; RAF, rapidly accelerated a fibrosarcoma; PDGFR/c-Kit, platelet-derived growth factor receptor/tyrosine-protein kinase KIT; FGFR, fibroblast growth factor receptor; RET, rearranged during transection; MET, receptor tyrosine kinase MET; AXL/FLT3/TRKB, receptor tyrosine kinase AXL/FMS like tyrosine kinase-3/tyrosine receptor kinases B; TIE2, tyrosine kinase with immunoglobulin-like loops and epithelial growth factor homology domain-2.

Table 3 Selected phase III studies determining the role of systemic treatment in earlier-stage hepatocellular carcinoma

	NCT number	Patient numbers	Study arm	Control arm	Primary end points
IMbrave050	04102098	668	Atezolizumab + bevacizumab	Active surveillance	RFS
EMERALD-2	03847428	877	Durvalumab + bevacizumab	Placebo	RFS
			Durvalumab
CHECKMATE 9DX	03383458	545	Nivolumab	Placebo	RFS
KEYNOTE 937	03867084	950	Pembrolizumab	Placebo	RFS
ABC-HCC	04803994	434	Atezolizumab + bevacizumab	TACE	TTF
RENOTACE	04777851	496	Regorafenib + nivolumab	TACE	PFS
TACE-3	04268888	522	Nivolumab + TACE	TACE	OS, TTTP*
LEAP-012	04246177	950	Pembrolizumab + lenvatinib + TACE	TACE	PFS, OS
CHECKMATE 74W	04340193	765	Nivolumab + ipilimumab + TACE	TACE	TTTP, OS
			Nivolumab + TACE
EMERALD-1	03778957	724	Durvalumab + bevacizumab + TACE	TACE	PFS
			Durvalumab + TACE
EMERALD-3	05301842	525	Durvalumab + tremelimumab + lenvatinib + TACE	TACE	PFS
			Durvalumab + tremelimumab + TACE

Note: *TTTP was the primary end point for the phase II part.

Abbreviations: NCT, National Clinical Trial; RFS, recurrence-free survival; TACE, transarterial chemoembolization; TTF, time to treatment failure; PFS, progression-free survival; TTTP, time to TACE progression.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857

 PubMed Web of Science ®Google Scholar

Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. doi:10.1016/S1470-2045(08)70285-7

 PubMed Web of Science ®Google Scholar

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173. doi:10.1016/S0140-6736(18)30207-1

 PubMed Web of Science ®Google Scholar

Qin S, Bi F, Gu S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase II-III trial. J Clin Oncol. 2021;39(27):3002–3011. doi:10.1200/JCO.21.00163

 PubMed Web of Science ®Google Scholar

Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90. doi:10.1016/S1470-2045(21)00604-5

 PubMed Web of Science ®Google Scholar

Kelley RK, Rimassa L, Cheng AL, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:995–1008. doi:10.1016/S1470-2045(22)00326-6

 PubMed Web of Science ®Google Scholar

Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22(7):977–990. doi:10.1016/S1470-2045(21)00252-7

 PubMed Web of Science ®Google Scholar

Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(4):379. doi:10.1200/JCO.2022.40.4_suppl.379

 Web of Science ®Google Scholar

Qin S, Chan LS, Gu S, et al. LBA35 camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial. Ann Oncol. 2022;33:S1401–S1402. doi:10.1016/j.annonc.2022.08.032

 Web of Science ®Google Scholar

Qin S, Kudo M, Meyer T, et al. LBA36 final analysis of RATIONALE-301: randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Ann Oncol. 2022;33:S1402–S1403. doi:10.1016/j.annonc.2022.08.033

 Web of Science ®Google Scholar

Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. doi:10.1016/S0140-6736(16)32453-9

 PubMed Web of Science ®Google Scholar

Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. doi:10.1056/NEJMoa1717002

 PubMed Web of Science ®Google Scholar

Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–296. doi:10.1016/S1470-2045(18)30937-9

 PubMed Web of Science ®Google Scholar

Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193–202. doi:10.1200/JCO.19.01307

 PubMed Web of Science ®Google Scholar

Qin SK, Chen ZD, Fang WJ, et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): phase 3 KEYNOTE-394 study. J Clin Oncol. 2022;40(4):4088. doi:10.1200/JCO.2022.40.16_suppl.4088

 Web of Science ®Google Scholar

Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol. 2006;33(5):S1–S7. doi:10.1053/j.seminoncol.2006.08.002

 PubMed Web of Science ®Google Scholar

Tian S, Quan H, Xie C, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011;102(7):1374–1380. doi:10.1111/j.1349-7006.2011.01939.x

 PubMed Web of Science ®Google Scholar

Wadhwa R, Taketa T, Sudo K, Blum-Murphy M, Ajani JA. Ramucirumab: a novel antiangiogenic agent. Future Oncol. 2013;9(6):789–795. doi:10.2217/fon.13.68

 PubMed Web of Science ®Google Scholar

Fuchs CS, Tomasek J, Cho JY, et al. REGARD: a phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line p. Cancer Res. 2013;73(8):LB–67. doi:10.1158/1538-7445.AM2013-LB-67

 Web of Science ®Google Scholar

Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745

 PubMed Web of Science ®Google Scholar

Mo H, Huang J, Xu J, et al. Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study. Br J Cancer. 2018;119(5):538–545. doi:10.1038/s41416-018-0100-3

 PubMed Web of Science ®Google Scholar

Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–3175. doi:10.1200/JCO.2009.26.7609

 PubMed Web of Science ®Google Scholar

Hoy SM. Sintilimab: first global approval. Drugs. 2019;79(3):341–346. doi:10.1007/s40265-019-1066-z

 PubMed Web of Science ®Google Scholar

Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14):8372–8377. doi:10.1073/pnas.1533209100

 PubMed Web of Science ®Google Scholar