Table 2.
Selected trials of immune-checkpoint–based combination therapy for hepatocellular carcinoma (HCC)
| NCT | Phase/Design | Setting/Line | Regimen (Arms) | Primary endpoint(s) | Key results (primary endpoints) | Notable AEs (≥ G3)/Safety |
|---|---|---|---|---|---|---|
| NCT03764293 (CARES-310) | Phase III, RCT | Unresectable HCC, 1 L | Camrelizumab + rivoceranib vs. sorafenib | OS, PFS | OS 22.1 mo; PFS 5.6 mo; ORR 26.8% (combo superior) | Hypertension; ↑AST/ALT |
| NCT03794440 | Phase II/III, RCT | Unresectable HCC (HBV+), 1 L | Sintilimab + bevacizumab biosimilar vs. sorafenib | OS (primary), PFS | PFS 4.6 vs. 2.8 mo; OS NR vs. 10.4 mo (favor combo) | Manageable; VEGF-class |
| NCT03713593 (LEAP-002) | Phase III, RCT | Unresectable HCC, 1 L | Lenvatinib + pembrolizumab vs. lenvatinib + placebo | OS, PFS (co-primary) | OS 21.2 vs. 19.0 mo; PFS 8.2 vs. 8.0 mo (NS) | Class-consistent; no new signals |
| NCT03937219 (COSMIC-312) | Phase III, RCT | Unresectable HCC, 1 L | Cabozantinib + atezolizumab vs. sorafenib | PFS (primary); OS (secondary) | PFS improved (HR 0.63); OS not statistically significant | TKI/VEGF-class AEs |
| NCT03298451 (HIMALAYA) | Phase III, RCT | Unresectable HCC, 1 L | STRIDE: tremelimumab (300 mg ×1) + durvalumab q4w vs. sorafenib | OS | 5-yr OS 19.6% vs. 9.4%; ORR 20.1% vs. 5.1% | Grade ≥ 3 irAEs ~ 17.5%; manageable |
| NCT01658878 (CheckMate-040, combo cohorts) | Ph 1/2, multi-arm | Advanced HCC, post-sorafenib | Nivolumab + ipilimumab (various doses) | ORR, OS | ORR ~ 27%; OS 12.5 mo; 36-mo OS 26% | Grade ≥ 3 AEs up to ~ 53% in high-ipilimumab arm |
| NCT04039607 (CheckMate-9DW) | Phase III, RCT | Unresectable HCC, 1 L | Nivolumab + ipilimumab vs. lenvatinib or sorafenib | OS | OS 23.7 mo; ORR 36% vs. 13%; DOR 30.4 vs. 12.9 mo | Immune hepatitis (fatal cases reported in program); overall manageable |
| NCT03778957 (EMERALD-1) | Phase III, RCT | Intermediate HCC (BCLC B), TACE-eligible | TACE + durvalumab + bevacizumab vs. TACE + placebos (and TACE + durvalumab) | PFS | Median PFS 15.0 vs. 8.2 mo (combo vs. control); ORR 43.6% vs. 29.6% | VEGF-class; manageable |
| NCT04246177 (LEAP-012) | Phase III, RCT | Intermediate HCC, TACE-eligible | TACE + lenvatinib + pembrolizumab vs. TACE + placebos | OS, PFS | PFS 14.6 mo; ORR 46.8% (reported) | Class-consistent |
| NCT03006926 | Phase 1b, single-arm | Unresectable HCC, 1 L | Lenvatinib + pembrolizumab | ORR, DOR (primary) | ORR 46%; DOR 8.6 mo; PFS 9.0 mo | No unexpected safety |
| NCT05185739 | Phase II, randomized (neoadj ± adj) | Resectable HCC | Pembrolizumab or lenvatinib or both (peri-op) | Major pathologic response | No results reported | — |
| NCT04425226 | Not App., prospective | Pre-transplant HCC (neoadjuvant) | Pembrolizumab + lenvatinib | Recurrence-free survival | 12-mo RFS 87.5% vs. 37.5% | Transplant-specific safety monitored |
| NCT04988945 | Phase II, single-arm | Unresectable HCC (downstaging) | TACE + SBRT → tremelimumab + anti-PD-L1 | Efficacy; safety | Results pending | — |
| NCT04611165 | Phase II, single-arm | Advanced HCC with macrovascular invasion | EBRT + nivolumab | PFS | PFS 5.6 mo; OS 15.2 mo; ORR 36%; DCR 74% | Grade ≥ 3 ~ 12% |
| NCT03380130 (NASIR-HCC) | Phase II, single-arm | Unresectable, liver-confined HCC | SIRT (Y-90) → nivolumab | Safety (primary), ORR/OS | ORR 40%; DCR 81%; OS 20.9 mo | SAEs 12%; discontinuation ~ 2.3% |
| NCT05528952 (TERTIO) | Phase II, RCT | Unresectable HCC, 1 L | Atezolizumab + bevacizumab ± UCPVax (anti-telomerase vaccine) | ORR | Ongoing; no results | — |
| NCT04251117 | Phase 1/2, single-arm | Advanced HCC | Personalized DNA vaccine (GNOS-PV02) + IL-12 plasmid + pembrolizumab | Safety; immunogenicity | ORR 30.6%; median OS 19.9 mo; injection-site reactions 41.6% | Acceptable |
| Real-world (no NCT) | Retrospective cohort | BCLC B/C | TACE + PD(L)1 + TKI/anti-VEGF vs. TACE | PFS (primary) | PFS 9.5 vs. 8.0 mo; OS 19.2 vs. 15.7 mo; ORR 60.1% vs. 32.0% | Acceptable |
Trials are organized by phase/design and clinical setting. For each study, the regimen, prespecified primary endpoint(s), and top-line results for primaries are shown; secondary outcomes are omitted unless explicitly highlighted in the manuscript text. Safety is summarized as grade ≥ 3 treatment-related adverse events. HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; PD-(L)1, programmed death-(ligand) 1; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy; SBRT, stereotactic body radiotherapy; SIRT/TARE, yttrium-90 radioembolization; TKI, tyrosine-kinase inhibitor; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival; DOR, duration of response; HR, hazard ratio; mo, months; NR, not reported.