| Immunotherapy: first line |
| IMbrave150 [118] | Atezolizumab plus bevacizumab vs. sorafenib | Overall (501)HBV (240, 48%)HCV (108, 22%)Non-viral (153, 31%) | 0.58 (0.42–0.79)0.51 (0.32–0.81)0.43 (0.22–0.87)0.91 (0.52–1.60) | 0.59 (0.47–0.76)0.47 (0.33–0.67)0.69 (0.39–1.20)0.71 (0.47–1.08) |
| COSMIC-312 [119] | Atezolizumab plus cabozantinib vs. sorafenib | Overall (649)HBV (190, 29%)HCV (202, 31%)Non-viral (257, 40%) | 0.90 (0.69–1.18)0.53 (0.33–0.87)1.10 (0.72–1.68)1.18 (0.78–1.79) | 0.63 (0.44–0.91)0.46 (0.29–0.73)0.64 (0.38–1.09)0.92 (0.60–1.41) |
| HIMALAYA [120] | Tremelimumab plus durvalumab vs. sorafenib | Overall (782)HBV (241, 31%)HCV (214, 27%)Non-viral (327, 42%) | 0.78 (0.65–0.93)0.64 (0.48–0.86)1.06 (0.76–1.49)0.74 (0.57–0.95) | 0.90 (0.77–1.05)--- |
| Durvalumab vs. sorafenib | Overall (778)HBV (238, 31%)HCV (211, 27%)Non-viral (329, 42%) | 0.86 (0.73–1.03)0.78 (0.58–1.04)1.05 (0.75–1.48)0.82 (0.64–1.05) | 1.02 (0.88–1.19)--- |
| CheckMate 459 [121] | Nivolumab vs. sorafenib | Overall (743)HBV (233, 31%)HCV (173, 23%)Non-viral (336, 45%) | 0.85 (0.72–1.02)0.77 (0.56–1.05)0.71 (0.49–1.01)0.95 (0.74–1.22) | 0.93 (0.79–1.10)--- |
| RATIONALE-301 [122] | Tislelizumab vs. sorafenib | Overall (674)HBV (427, 63%)HCV (85, 13%)Non-viral (162, 24%) | 0.85 (0.71–1.02)0.91 (0.73–1.14)0.64 (0.38–1.08)0.78 (0.55–1.12) | 1.11 (0.92–1.33)--- |
| LEAP-002 [123] | Pembrolizumab plus lenvatinib vs. lenvatinib | Overall (794)HBV (385, 47%)HCV (181, 22%)Alcohol (251, 31%) | 0.84 (0.71–1.00)0.75 (0.58–0.97)0.86 (0.60–1.24)0.84 (0.67–1.05) | 0.83 (0.71–0.98)--- |
| CARES-310 [124] | Camrelizumab plus rivoceranib vs. sorafenib | Overall (543)HBV (405, 75%)HCV (51, 9%)Non-viral (87, 16%) | 0.62 (0.49–0.80)0.66 (0.50–0.87)0.45 (0.18–1.16)0.71 (0.37–1.36) | 0.52 (0.41–0.65)0.57 (0.45–0.72)0.46 (0.21–1.05)0.55 (0.33–0.93) |
| ORIENT-32 [125] | Sintilimab plus IBI305 vs. sorafenib | Overall (571)HBV (538, 94%)Non-HBV (33, 6%) | 0.57 (0.43–0.75)0.58 (0.43–0.76)0.80 (0.22–2.87) | 0.56 (0.46–0.70)0.56 (0.40–0.76)0.38 (0.14–1.06) |
| Immunotherapy: second line |
| KEYNOTE-240 [126] | Pembrolizumab vs. placebo | Overall (413)HBV (101, 24%)HCV (64, 15%)Non-viral (248, 60%) | 0.78 (0.61–1.00)0.57 (0.35–0.94)0.96 (0.48–1.92)0.88 (0.64–1.20) | 0.72 (0.57–0.90)0.70 (0.44–1.13)0.46 (0.24–0.90)0.75 (0.56–1.01) |
| KEYNOTE-394 [127] | Pembrolizumab vs. placebo | Overall (453)HBV (360, 79%)Non-HBV (93, 21%) | 0.79 (0.63–0.99)0.78 (0.61–0.99)0.87 (0.53–1.44) | 0.74 (0.60–0.92)0.77 (0.61–0.98)0.58 (0.36–0.94) |
| Tyrosine kinase inhibitors: first line |
| SHARP [128,129] | Sorafenib vs. placebo | Overall (439)HBV (111, 18%)HCV (169, 28%)Alcohol (159, 26%) | 0.69 (0.55–0.87)0.76 (0.38–1.50)0.50 (0.32–0.77)0.76 (0.50–1.16) | ---- |
| Asia–Pacific [130,131] | Sorafenib vs. placebo | Overall (226)HBV (165, 73%)Non-HBV (61, 27%) | 0.68 (0.50–0.93)0.74 (0.51–1.06)0.57 (0.29–1.13) | --- |
| REFLECT [132] | Lenvatinib vs. sorafenib | Overall (753)HBV (479, 50%)HCV (217, 23%)Alcohol (57, 6%) | 0.92 (0.79–1.06)0.83 (0.68–1.02)0.91 (0.66–1.26)1.03 (0.47–2.28) | 0.66 (0.57–0.77)0.62 (0.50–0.75)0.78 (0.56–1.09)0.27 (0.11–0.66) |
| Tyrosine kinase inhibitors: second line |
| CELESTIAL [133] | Cabozantinib vs. placebo | Overall (707)HBV (267, 38%)HCV (168, 24%)Non-viral (272, 38%) | 0.76 (0.63–0.92)0.69 (0.51–0.94)1.11 (0.72–1.71)0.72 (0.54–0.96) | 0.44 (0.36–0.52)0.31 (0.23–0.42)0.61 (0.42–0.88)0.48 (0.36–0.63) |
| RESORCE [134] | Regorafenib vs. placebo | Overall (573)HBV (216, 38%)HCV (119, 21%)Alcohol (145, 25%) | 0.63 (0.50–0.79)0.58 (0.41–0.82)0.79 (0.49–1.26)0.92 (0.61–1.38) | 0.46 (0.37–0.56)0.39 (0.29–0.54)0.59 (0.39–0.90)0.53 (0.37–0.77) |
| REACH-2 [135] | Ramucirumab vs. placebo | Overall (292)HBV (107, 37%)HCV (76, 26%)Other (109, 37%) | 0.71 (0.53–0.95)0.84 (0.52–1.35)0.76 (0.44–1.33)0.63 (0.38–1.06) | 0.45 (0.34–0·60)0.43 (0.28–0.68)0.33 (0.19–0.60)0.57 (0.35–0.95) |