Research progress regarding programmed cell death 1/programmed cell death ligand 1 inhibitors combined with targeted therapy for treating hepatocellular carcinoma

Table 1 Combination therapy for hepatocellular carcinoma

Combination therapy	Trial name	Phase	Number of patients	Control	Outcome (months or rate)	Ref.
Lenvatinib + pembrolizumab	KEYNOTE-524	Ib	100	None	ORR: 46% by mRECIST and 36% by RECIST v1.1; mPFS: 9.3 mo by mRECIST and 8.6 mo by RECIST v1.1; mOS: 22.0 mo	Finn et al[29]
Lenvatinib + nivolumab	Study-117	Ib	30	None	ORR: 76.7%, DCR: 96.7%, CBR: 83.3%	Kudo et al[30]
Avelumab + axitinib	VEGF liver-100	Ib	22	None	mOS: 12.7 mo, 1-yr OS rate: 54.5%; ORR: 13.6% by RECIST v1.1 and 31.8% by mRECIST	Kudo et al[31]
Pembrolizumab + regorafenib	KN-743	Ib	36	None	ORR: 28%, DCR: 91%	Galle et al[32]
Camrelizumab + apatinib	RESCUE	II	190	None	ORR for first- and second-line treatment: 34.3% and 22.5%, mPFS: 5.7 and 5.5 mo; 12-mo OS rate: 74.7% and 68.2%	Xu et al[33]
Atezolizumab + bevacizumab	IMbrave150	III	501	Sorafenib	mOS: 19.2 mo vs 13.4 mo; mPFS: 6.9 mo vs 4.3 mo	Finn et al[34]
Lenvatinib + pembrolizumab	LEAP-002	III	750	Lenvatinib + placebo	Ongoing	Llovet et al[35]
camrelizumab + apatinib	NCT03764293	III	510	Sorafenib	Ongoing	National Cancer Institute[36]
Cabozantinib + atezolizumab	COSMIC-312	III	740	Sorafenib or cabozantinib	Ongoing	Kelley et al[37]

CBR: Clinical benefit rate; DCR: Disease control rate; HCC: Hepatocellular carcinoma; HR: Hazard ratio; MOS: Median overall survival; MPFS: Median progression-free survival; MRECIST: Modified response evaluation criteria in solid tumors; RECIST v1.1: Response evaluation criteria in solid tumors version 1.1; NE: Not estimable; ORR: Objective response rate; OS: Overall survival; VEGF: Vascular endothelial-derived growth factor.

Table 2 Grade 3/4 adverse events in combination therapy groups

Combination therapy group	Phase	Grade 3/4 adverse events (%)
Lenvatinib + pembrolizumab group (n = 100)	Ib	Hypertension (17), AST increased (11), diarrhea (5), asthenia (5), fatigue (4)
Lenvatinib + nivolumab group (n = 30)	Ib	Palmar-plantar erythrodysesthesia (56.7), dysphonia (53.3)
Avelumab + axitinib group (n = 22)	Ib	Hypertension (50.0), HFSR (22.7)
Pembrolizumab + regorafenib group (n = 36)	Ib	AST increase (19), ALT increase (14), hypertension (14), bilirubin increase (14), lipase increase (11)
Camrelizumab + apatinib group (n = 190)	II	Hypertension (34.2), gamma-glutamyltransferase increase (11.6), neutropenia (11.1)
Atezolizumab + bevacizumab group (n = 329)	III	Hypertension (15.2), AST increase (7.0), ALT increase (3.6), platelet count decrease (3.3), proteinuria (3.0)
Lenvatinib + pembrolizumab group	III	Ongoing
Camrelizumab + apatinib group	III	Ongoing
Cabozantinib + atezolizumab group	III	Ongoing

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; HFSR: Hand–foot skin reaction.