Post-immunotherapy second-line strategies for hepatocellular carcinoma: State of the art and ongoing trials

Table 1 Ongoing clinical trials of immune checkpoint inhibitors-based second-line systemic treatments for hepatocellular carcinoma

Study	Status	Description	Phase	Study design	Treatment arms	Number of patients	Population	Primary endpoint
NCT04770896 (imbrave 251)	Active, not recruiting	A study of atezolizumab with lenvatinib or sorafenib vs lenvatinib or sorafenib alone in hepatocellular carcinoma previously treated with atezolizumab and bevacizumab	Phase 3	RCT	Atezolizumab + lenvatinib or sorafenib; lenvatinib or Sorafenib	554	Progressed on atezo-bev; Child-Pugh A; PS 0-1	OS
NCT05168163	Recruiting	Atezolizumab in combination with a multi-kinase inhibitor for the treatment of unresectable, locally advanced, or metastatic liver cancer	Phase 2	RCT	Atezolizumab + cabozantinib or Lenvatinib; cabozantinib or lenvatinib	122	Progressed on atezo-bev; Child-Pugh A, PS 0-1	OS, PFS
NCT05822752	Active, not recruiting	Study to evaluate adverse events, and change in disease activity, when IV infused with livmoniplimab in combination with IV infused budigalimab in adult participants with HCC	Phase 2	RCT	Lenvatinib or sorafenib; livmoniplimab dose A + budigalimab; livmoniplimab dose B + budigalimab	130	Progressed on ICI regimens; Child-Pugh A; PS 0-1	BOR
NCT04696055	Completed	An open-label study of regorafenib in combination with pembrolizumab in patients with advanced or metastatic HCC After PD1/PD-L1 immune checkpoint inhibitors	Phase 2	Single-arm	Pembrolizumab + regorafenib	95	Progressed on ICIs regimens; Child-Pugh A, PS 0-1	ORR
NCT05101629	Active, not recruiting	Pembrolizumab and lenvatinib in patients with advanced HCC who are refractory to atezolizumab and bevacizumab/io-based therapy	Phase 2	Single-arm	Pembrolizumab + lenvatinib	32	Progressed on atezo-bev; Child-Pugh A; PS 0-1	ORR
NCT05199285	Recruiting	A phase II study of nivolumab + ipilimumab in advanced HCC patients who have progressed on first line atezolizumab + bevacizumab	Phase 2	Single-arm	Nivolumab + ipilimumab	40	Progressed on atezo-bev; Child-Pugh A; PS 0-1	ORR
NCT05257590	Recruiting	CVM-1118 in combination with nivolumab for unresectable advanced hepatocellular carcinoma	Phase 2	Single-arm	Nivolumab + CVM-1118	31	Progressed on atezo-bev or TKIs; child Pugh A, PS 0-1	ORR
NCT05178043	Active, not recruiting	GT90001 plus nivolumab in patients with advanced hepatocellular carcinoma	Phase 2	Single-arm	Nivolumab + GT90001	5	Progressed on ICI or ICI + TKI; Child-Pugh A; PS 0-1	ORR

NCT: National clinical trial; HCC: Hepatocellular carcinoma; IV: Intravenously; PD-1: Programmed death-1; PD-L1: Programmed cell death ligand 1; RCT: Randomized clinical trial; ICIs: Immune checkpoint inhibitors; PS: Performance status; TKI: Tyrosine kinase inhibitor; OS: Overall survival; PFS: Progression-free survival; BOR: Best overall response; ORR: Objective response rate; atezo-bev: Atezolizumab-bevacizumab.

Table 2 Concluded retrospective and prospective studies investigating the efficacy and safety of tyrosine kinase inhibitors as a second-line treatment after progression to first-line immune checkpoint inhibitors

Treatment	Prior treatment	Ref.	Patients (number)	Region	Study design	Child Pugh-A (%)	BCLC-C (%)	MVI (%)	Extrahepatic spread (%)	mPFS (months)	mOS (months)	ORR (%)	DCR (%)	Gr3/4 TRAE (%)
Sora, lenva, cabo	AB	Yoo et al[37]	49	Asia	Retrospective	100	100	38.8		6.1 (lenva); 2.5 (sora)	16.6 (lenva); 11.2 (sora)	15.8 (lenva); 0 (sora)	62.1 (lenva); 63.2 (sora)	16.3
Cabo	ICIs	Storandt et al[38]	26	United States	Retrospective	72				2.1	7.7	4	27	27
Rego vs other mTKIs (sora, lenva, cabo)	AB	Falette-Puisieux et al[39]	82	France	Retrospective	82.9	92.7	37.8	80.5	2.6 (rego); 2.8 (other mTKIs)	15.8 (rego); 7.0 (other mTKIs)			17.2 (rego); 28.3 (other mTKIs)
Sora	AB	Tovoli et al[29]	40	Italy	Retrospective	87.5		42.5	60	3.3	6.9	0	10
Sora vs lenva	AB	Chon et al[40]	126	Korea	Retrospective	72.2	86.6	46	69	3.5 (lenva); 1.8 (sora)	10.3 (lenva); 7.5 (sora)	7.5 (lenva); 5.8 (sora)	67.5 (lenva); 24.4 (sora)	35 (lenva); 38.4 (sora)
Rego	AB	Yoo et al[43]	40	Asia	Prospective	100	97.5			3.5	9.7	10	82.5
Cabo	ICIs	Chan et al[41]	47	Asia	Prospective	100	93.6	30		4.3 (II line); 4.0 (III line)	14.3 (II line); 6.6 (III line)	6.4	83.1
Lenva	AB	Yoo et al[45]	50	Korea	Prospective	100	76	24		5.4	8.6	12	84

cabo: Cabozantinib; sora: Sorafenib; lenva: Lenvatinib; rego: Regorafenib; mTKIs: Multitarget tyrosine kinase inhibitors; AB: Atezolizumab plus bevacizumab; ICIs: Immune checkpoint inhibitors; BCLC: Barcelona Clinic Liver Cancer; MVI: Macrovascular invasion; mOS: Median overall survival; mPFS: Median progression-free survival; DCR: Disease control rates; ORR: Objective response rates; Gr3/4 TRAE: Grade 3/4 treatment related adverse event.

Table 3 Ongoing clinical trials of tyrosine kinase inhibitors as second-line systemic treatments for hepatocellular carcinoma following progression to immune checkpoint inhibitors

Study	Status	Description	Phase	Study design	Treatment arms	Number of patients	Population	Primary endpoint
NCT06138769	Active, not recruiting	Lenvatinib after progression on atezolizumab-bevacizumab in hepatocellular carcinoma	Phase 2	Single-arm	Lenvatinib	50	Progressed on atezo-bev; Child-Pugh A; PS 0-1	PFS
NCT04767906 (capture)	Completed	Cabozantinib treatment in a phase II study for patients with hepatocellular carcinoma refractory to PD-1 inhibitors	Phase 2	Single-arm	Cabozantinib	40	Progressed on PD-1 or PD-L1 inhibitor; Child-Pugh A; PS 0-1; BCLC B/C	ToT
NCT04511455	Completed	Cabozantinib for patients with hepatocellular carcinoma refractory to first line treatment	Phase 2	Single-arm	Cabozantinib	22	Progressed on lenvatinib or lenvatinib + ICIs; Child-Pugh A-B7; PS 0-1	ToT
NCT0653573 (Child-Pugh AB)	Not yet recruiting	A phase 2, single arm study of cabozantinib in patients with hepatocellular carcinoma who have received prior atezolizumab and bevacizumab	Phase 2	Single-arm	Cabozantinib	40	Progressed on atezo-bev; Child-Pugh A-B7; PS 0-1	DCR
NCT06446154	Recruiting	Fruquintinib after ICIs treatment in unresectable hepatocellular carcinoma	Phase 2	Single-arm	Fruquintinib	36	Progressed on ICIs; Child-Pugh A-B7; PS 0-1	ORR
NCT05134532	Unknown status	Regorafenib after progression on atezolizumab plus bevacizumab in advanced hepatocellular carcinoma	Phase 2	Single-arm	Regorafenib	40	Progressed on atezo-bev; Child-Pugh A; PS 0-1	PFS
NCT04435977	Unknown status	Efficacy and safety of cabozantinib in patients with hepatocellular carcinoma	Phase 2	Single-arm	Cabozantinib	46	Progressed on ICIs; Child-Pugh A; PS 0-1	PFS

NCT: National clinical trial; PD-1: Programmed death-1; ICIs: Immune checkpoint inhibitors; atezo-bev: Atezolizumab-bevacizumab; PS: Performance status; PD-L1: Programmed cell death ligand 1; BCLC: Barcelona Clinic Liver Cancer; PFS: Progression-free survival; DCR: Disease control rates; ToT: Time-on-treatment; ORR: Objective response rates.