Combination approaches in hepatocellular carcinoma: How systemic treatment can benefit candidates to locoregional modalities

Table 1 Clinical trials in advanced hepatocellular carcinoma with combination of systemic treatment

Study name	Design	Experimental arm	Median overall survival, mo	Response rate- RECIST, %	Grade 3 - 4 treatment-related adverse events
IMBRAVE 150[21]	Phase III; First-line	Atezolizumab + Bevacizumab	19.2	30%	36%
KEYNOTE 524/Study 116[22]	Phase Ib; First-line	Pembrolizumab + Lenvatinib	22	36%	67%
REG-PEMBRO-HCC[23]	Phase Ib; First-line	Pembrolizumab + Regorafenib	26.5	32%	86%
CHECKMATE 040[24]	Phase II; Second-line	Nivolumab + Ipilimumab (arm A)	22.8	32%	53%
STUDY 22[27]	Phase II; Second-line	Durvalumab + Tremelimumab	18.7	24%	35.1%
CHECKMATE-040[25]	Phase II; First and second-line	Nivolumab + Ipilimumab + Cabozantinib	Not-reached	26%	71%

Table 2 Clinical trials approaching combination of systemic treatment and ablation enrolling, recruiting, or waiting for final results

Trial	Trial registration	Drug	Control	n	Disease stage	Local treatment	Expected termination	Primary end-point
CHECKMATE 9DX	NCT03383458	Nivolumab	Placebo	530	Early/intermediate	Surgery/Ablation	2025	Recurrence-free survival
KEYNOTE 937	NCT03867084	Pembrolizumab	Placebo	950	Early/intermediate	Surgery/Ablation	2025	Recurrence-free survival and overall survival
IMBRAVE 050	NCT04102098	Atezolizumab + Bevacizumab	Surveillance	662	Early/intermediate /advanced	Surgery/Ablation	2027	Recurrence-free survival
EMERALD-2	NCT03847428	Durvalumab + Bevacizumab	Placebo	888	Early/intermediate	Surgery/Ablation	2024	Recurrence-free survival

Table 3 Clinical trials approaching combination of systemic treatment and intra-arterial actually enrolling, recruiting or waiting for final results

Trial	Trial registration	Drug	Control	n	Disease stage	Local treatment	Expected termination	Primary end-point
EMERALD-1	NCT03778957	Durvalumab + Bevacizumab plus TACE	TACE plusplacebo	600	Intermediate/advanced	TACE	2024	Progression-free survival
TACE-3	NCT04268888	Nivolumab plus DEB- TACE	DEB- TACE	522	Intermediate	DEB-TACE	2026	Overall survival
LEAP-012	NCT04246177	Lenvatinib plus Pembrolizumab plus cTACE	cTACE	950	Intermediate	Surgery/Ablation	2029	Overall survival and progression-free survival
CheckMate 74 W	NCT04340193	Nivolumab plusIpilimumab/placebo plus cTACE	cTACE plusplacebo	765	Intermediate	Surgery/Ablation	Non-available	Time-to-progression and overall survival

c: Conventional; DEB: Drug-eluting beads; TACE: Transarterial chemoembolization.