Table 3.
Summary of Efficacy and Safety of the Approved Systemic Therapies for aHCC
| Source | Targets | Treatment (No. of Patients) | Main Efficacy and Safety Results | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| OS | PFS | ORR | Grade ≥3 TRAEs | |||||||
| Median (Months) | HR (95% CI) | P value | Median (Months) | HR (95% CI) | P value | |||||
| First-line | ||||||||||
| SHARP(2007), Llovet et al15 | VEGFRs, PDGFR-β, | Sorafenib (297) 400 mg bid. vs | 10.7 vs 7.9 | 0.69 (0.55–0.87) | <0.001 | 5.5 vs 2.8 | 0.58(0.45–0.74) | <0.001 | 2% vs 1%(RECIST v1.1) | 80% vs 52% ‡ |
| c-Kit, FLT3, RET | Placebo (302) | |||||||||
| REFLECT (2018), Kudo et al16 | VEGFR1-3, FGFR1-4, PDGFR-α, | Lenvatinib (478) 12 mg (>60 kg), 8 mg (<60 kg) qd. vs | 13.6 vs 12.3 | 0.92 (0.79–1.06) | NA | 7.4 vs 3.7 | 0.66(0.57–0.77) | <0.0001 | 40.6% vs 12.4% (mRECIST) | 75% vs 67% |
| RET, c-Kit | Sorafenib (476) 400 mg bid. | 18.8% vs 6.5% (RECIST v1.1) | ||||||||
| CheckMate 459 (2019), Yau et al141 | PD-1 | Nivolumab (371) 240 mg q2w. vs | 16.4 vs 14.7 | 0.85 (0.72–1.02) | 0.08a | 3.7 vs 3.8 | 0.93 (0.79–1.10) | NA | 15% vs 7% (RECIST v1.1) | 22% vs 49% |
| Sorafenib (372) 400 mg bid. | ||||||||||
| IMbrave 150 (2020), Finn et al22,193 | PD-L1+VEGF | Atezolizumab 1200 mg+bevacizumab 15mg/kg, q3w (336) vs | 19.2 vs 13.4 | 0.66 (0.52–0.85) | <0.001b | 6.8 vs 4.3 | 0.59 (0.47–0.76) | <0.001b | 27.3% vs 11.9% (RECIST v1.1) | 36% vs 46% |
| Sorafenib (165) 400 mg bid. | 33.2% vs 13.3% (mRECIST) | |||||||||
| Second-line | ||||||||||
| RESORCE (2017), Bruix et al17 | VEGFR, PDGFR, BRAF, KIT, | Regorafenib (379) 160 mg qd.vs | 10.7 vs 7.8 | 0.63 (0.50–0.79) | <0.0001 | 3.1 vs 1.5 | 0.46(0.37–0.56) | <0.0001 | 11% vs 4% (mRECIST) | 67% vs 39% |
| RET, RAF-1, FGFR, Tie-2 | Placebo (194) | |||||||||
| CELESTIAL (2019), Abou-Alfa et al18 | VEGFR, MET, AXL, RET | Cabozantinib (470) 60 mg qd. vs | 10.2 vs 8.0 | 0.76 (0.63–0.92) | 0.005 | 5.2 vs 1.9 | 0.44(0.36–0.52) | <0.001 | 4% vs 0.4%(RECIST v1.1) | 67.7% vs 36.3% |
| Placebo (237) | ||||||||||
| REACH-2 (2019), Zhu et al19 | VEGFR 2 | Ramucirumab (197) 8 mg/kg, q2w. vs | 8.5 vs 7.3 | 0.71 (0.53–0.95) | 0.0199a | 2.8 vs 1.6 | 0.45(0.34–0.60) | <0.0001 | 5% vs 1% (RECIST v1.1) † | 11% vs 5% ‡ |
| Placebo (95) | ||||||||||
| KEYNOTE-240 (2020), Finn et al153 | PD-1 | Pembrolizumab (278) 200mg q3w. vs | 13.9 vs 10.6 | 0.78(0.61–0.998) | 0.02a | 3.0 vs 2.8 | 0.78 (0.61–0.99) | 0.02a | 18.3% vs 4.4% (RECIST v1.1) | 18.6% vs 7.5% |
| Placebo (135) | ||||||||||
| CheckMate-040 (2020), Yau et al212 | PD-1+CTLA-4 | Nivolumab 1mg/kg+Ipilimumab 3mg/kg, q3w. (50)* vs | 22.8 vs 12.5 vs 12.7 | NA | NA | NA | NA | NA | 32%vs31%vs31%(RECIST v1.1) | 53% vs29% vs31% |
| Nivolumab 3mg/kg+Ipilimumab 1mg/kg, q3w. (49)* vs | 34%vs33%vs31%(mRECIST) | |||||||||
| Nivolumab 3mg/kg q2w.+Ipilimumab 1mg/kg, q6w. (49) | ||||||||||
Notes: a primary end points not met; b primary end points met; * four doses followed by nivolumab 240mg q2w; † not significant; ‡ Any grade.
Abbreviations: aHCC, hepatocellular carcinoma; OS, overall survival; PFS, progression-free survival; ORR, overall response rate; HR, hazard ratio; TRAEs, treatment-related adverse events; NA, not available; mRECIST, modified Response Evaluation Criteria in Solid Tumors; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; qd, once daily; bid, twice daily; q2w, once every 2 weeks; q3w, once every 3 weeks; q6w, once every 6 weeks.