Systemic treatment of hepatocellular carcinoma secondary to non-alcoholic fatty liver disease

Table 1 Phase 3 studies of systemic treatment of hepatocellular carcinoma

Trial	Line	Treatment arm	HCC aetiology1	N (%)2	OS HR (95%CI)
ICI monotherapy
Checkmate-459[52]	1	Nivolumab (vs sorafenib)	Non-viral	168 (45)	0.95 (0.74-1.22)
			NAFLD/NASH	N/A
			HBV		0.77 (0.56-1.05)
			HCV		0.71 (0.49-1.01)
Keynote 240[46]	2	Pembrolizumab (vs placebo)	Non-viral	163 (59)	0.88 (0.64-1.20)
			NAFLD/NASH	N/A
			HBV		0.57 (0.35-0.94)
			HCV		0.96 (0.48-1.92)
RATIONALE-301[51]	1	Tislelizumab (vs sorafenib)	Non-viral	82 (24)	0.78 (0.55-1.12)
			NAFLD/NASH	N/A
			HBV		0.91 (0.73-1.14)
			HCV		0.64 (0.38-1.08)
Combination ICI + anti-VEGF
IMbrave150[40,44]	1	Atezolizumab + bevacizumab (vs sorafenib)	Non-viral	100 (30)	1.05 (0.68-1.63)
			NAFLD/NASH	N/A
			HBV		0.51 (0.32.081)
			HCV		0.43 (0.22-0.87)
Combination ICI + TKI
COSMIC-312[47]	1	Atezolizumab + cabozantinib (vs sorafinib)	Non-viral	169 (39)	1.18 (0.78-1.79)3
			NAFLD/NASH	38 (15)	Not reported
			HBV	74 (30)	0.53 (0.33-0.87)3
			HCV	34 (28)	1.1 (0.72-1.68)3
CARES-310[50]	1	Camrelizumab + rivoceranib (vs sorafenib) P3, 1L	Non-viral	42 (15)	0.71 (0.37-1.36)
			NAFLD/NASH	N/A
			HBV	208 (76)	0.66 (0.50-0.87)
			HCV	22 (8)	0.45 (0.18-1.16)
LEAP-002[45]	1	Pembrolizumab + lenvatinib (vs lenvatinib) P3, 1L	Not reported	N/A	N/A
Combination ICI + ICI
Himalaya[41]	1	Durvalumab + tremelimumab (vs sorafenib) P3, 1L	Non-viral	161 (41)	0.74 (0.57-0.95)
			NAFLD/NASH	N/A
			HBV	122 (31)	0.64 (0.48-0.86)
			HCV	110 (28)	1.06 (0.76-1.49)
TKI monotherapy
SHARP[49]	1	Sorafenib (vs placebo)	Non-viral	107 (35)	Not reported
			NAFLD/NASH	N/A
REFLECT[48]	1	Lenvantinib (vs sorafenib)	Non-viral	74 (16)	Reported only for alcohol
			NAFLD/NASH	N/A
RESORCE[43]	2	Regorafenib (vs placebo)	Non-viral	143 (38)	Reported only for alcohol
			NAFLD/NASH	N/A	Not reported
CELESTIAL[42]	2	Cabozantinib (vs placebo)	Non-viral	179 (38)	0.72 (54-0.96)
			NAFLD/NASH	43 (9)	Not reported
			HBV		0.69 (0.51-0.94)
			HCV		1.11 (0.72-1.71)
Anti-VEGF monotherapy
REACH-2[53]	2	Ramucirumab (vs placebo)	Non-viral	72 (37)	0.63 (0.38-1.06)
			NAFLD/NASH	19 (10)	Not reported
			HBV		0.84 (0.52-1.35)
			HCV		0.76 (0.44-1.33)

¹SHARP, REFLECT - alcohol, other; RESORCE, CELESTIAL - alcohol, other, non-alcoholic steatohepatitis (NASH); REACH-2 - alcohol, NASH, primary biliary cirrhosis, hereditary hemochromatosis, hepatitis non-A, non-B, non-C virus; Checkmate-459, Keynote 240, RATIONALE-301 - uninfected; IMbrave150 - alcohol, other, non-hepatitis B and C causes; COSMIC-312 - alcohol, non-alcoholic fatty liver, NASH, other; CARES-301 - NAFLD, alcohol cirrhosis, aflatoxin exposure, other unknown non-hepatitis B virus and non-hepatitis C virus causes; Himalaya - No active viral hepatitis identified.

²Number of patients in treatment arms; those with unknown aetiology were excluded where possible.

³Interim analysis.

HCC: Hepatocellular carcinoma; OS: Overall survival; HR: Hazard ratio; 95%CI: 95% confidence interval; ICI: Immune checkpoint inhibitor; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; HBV: Hepatitis B virus; HCV: Hepatitis C virus; N/A: Not applicable; VEGF: Vascular endothelial growth factor; TKI: Tyrosine kinase inhibitor.