Table 1 Published and ongoing phase III randomized control trials using immune checkpoint inhibitors in unresectable or metastatic hepatocellular carcinoma
Trial | Year publication or estimated completion | Tested therapy | Targets | Population | Result/main outcome | FDA Approved |
|---|---|---|---|---|---|---|
Published | ||||||
First line (advanced stage) | ||||||
IMbrave 150 | 2020 | Atezolizumab + Bevacizumab vs Sorafenib | PD-L1 + VEGF | Locally advanced or metastatic HCC, Child A | improved OS and PFS vs Sorafenib | Yes |
ORIENT-32 | 2021 | Sintilimab + Bevacizumab vs Sorafenib | PD-1 + VEGF | Cyto/Histopathological diagnosis, Chinese population, HBV associated HCC, Child A/B7 | Improved OS and PFS vs Sorafenib | No |
COSMIC-312 | 2022 | Atezolizumab + Cabozantinib vs Sorafenib | PD-L1 + multikinase | HCC on cirrhosis, not other curative or loco-regional therapies, Child A | Longer PFS in the Atezolizumab/Cabozantinib group, no differences in OS | No |
HIMALAYA | 2022 | Durvalumab + Tremelimumab or Durvalumab vs Sorafenib | PD-L1 + CTLA-4 | Histopathological confirmation, Child A | Improved OS than sorafenib. Durvalumab only was not inferior to Sorafenib | Yes |
CheckMate 459 | 2022 | Nivolumab vs sorafenib | PD-1 | Histopathological diagnosis, possible previous surgery or loco-regional treatments, Child A | No differences in OS | Yes |
CARES-310 | 2023 | Camrelizumab + Rivoceranib vs Sorafenib | PD-1 + VEGFR2 | Cyto/Histopathological diagnosis, Child A | Benefit in PFS and OS compared with sorafenib | No |
LEAP-002 | 2023 | Pembrolizumab + Lenvatinib vs Lenvatinib + placebo | PD-1 + multikinase | No loco-regional or curative possibilities, Child A | No difference in OS and PFS versus Lenvatinib plus placebo | No |
RATIONALE-301 | 2023 | Tislelizumab vs Sorafenib | PD-1 | Histopathological confirmation, Child A | Similar OS, a higher objective response rate in Tislelizumab, longer PFS with sorafenib | No |
Second line or more (advanced stage) | ||||||
KEYNOTE-240 | 2020 | Pembrolizumab vs placebo | PD-1 | Prior Sorafenib | Favorable risk-to-benefit ratio for pembrolizumab, no statistical difference for OS and PFS | Yes |
KEYNOTE-394 | 2022 | Pembrolizumab vs placebo | PD-1 | Prior Sorafenib or oxaliplatin-based CT, patients from Asia | Pembrolizumab improved OS and PFS | Yes |
Currently ongoing | ||||||
Adjuvant therapy | ||||||
JUPITER-04 (NCT 03859128) | 2023 | Toripalimab vs placebo | PD-1 | Adjuvant therapy in resected HCC with high risk of recurrence | RFS | |
RANT (NCT 05277675) | 2023 | Tislelizumab (or Sintilimab) + Lenvatinib (or Bevacizumab) + RFA vs RFA | PD-1 + | Neoadjuvant therapy, no possibility of resection, BCLC-0 or A, Child A/B7 | RFS | |
PREVENT-2 (NCT05910970) | 2024 | Tislelizumab + Lenvatinib vs Tislelizumab | PD-1 + multikinase | Adjuvant therapy in HCC at high risk of recurrence after resection or ablation, Child A-B7 | RFS | |
CheckMate 9DX (NCT 03383458) | 2025 | Nivolumab vs placebo | PD-1 | Adjuvant therapy in resected or ablated HCC with high risk of recurrence, Child A | RFS | |
EMERALD-2 (NCT03847428) | 2025 | Durvalumab + Bevacizumab vs Durvalumab + placebo vs placebo | PD-L1 + VEGF | Adjuvant therapy in resected or ablated HCC with high risk of recurrence | RFS | |
IMbrave 050 (NCT04102098) | 2027 | Atezolizumab + Bevacizumab vs surveillance | PD-L1 + VEGF | Adjuvant therapy in HCC at high risk of recurrence after resection or ablation | RFS | |
KEYNOTE-937 (NCT 03867084) | 2029 | Pembrolizumab vs placebo | PD-1 | Adjuvant therapy in cases with complete radiologic response after resection or ablation | RFS, OS | |
Intermediate stage | ||||||
CheckMate 74 W (NCT04340193) | 2024 | Nivolumab + Ipilimumab vs Nivolumab vs placebo, all in combination with TACE | PD-1 + CTLA-4 | Eligible patients for TACE | Safety | |
NCT04229355 | 2023 | Sorafenib vs Lenvatinib vs PD-1 Inhibitor, all in combination with DEB-TACE | PD-1 + multikinase | Unresectable HCC, Child A | PFS | |
ABC-HCC (NCT04803994) | 2025 | Atezolizumab + Bevacizumab vs TACE | PD-L1 + VEGF | No curative options, Child A, possible previous resection/ ablation/ TACE | Time to failure | |
TACE-3 (NCT04268888) | 2026 | Nivolumab vs placebo, all in combination with TACE/TAE | PD-1 | Child A, no indication for resection/ transplantation | OS | |
EMERALD-1 (NCT03778957) | 2026 | Durvalumab + TACE* followed by Durvalumab, Durvalumab + TACE* followed by Durvalumab + Bevacizumab, TACE only | PD-L1 | Child A or B7, not candidate for surgery | PFS | |
REPLACE (NCT04777851) | 2027 | Pembrolizumab + Regorafenib vs TACE or TARE | PD-1 + multikinase | Child A, ALBI 1–2, no contraindication to intra-arterial treatments | PFS | |
LEAP-012 (NCT04246177) | 2029 | Pembrolizumab + Lenvatinib vs placebo, all in combination with TACE | PD-1 | Incurable/ Non-metastatic HCC | PFS | |
First line (advanced stage) | ||||||
NCT03605706 | 2023 | Camrelizumab + FOLFOX4 vs FOLFOX4 + placebo | PD-1 | Child A/B7 | OS | |
CheckMate 9DW (NCT04039607) | 2026 | Nivolumab + Ipilimumab vs standard of care (Sorafenib or Lenvatinib) | PD-1 + CTLA-4 | Child A, no brain metastasis | OS | |
TRIPLET (NCT05665348) | 2026 | Atezolizumab + Bevacizumab with or without Ipilimumab | PD-L1 + CTLA-4 | No curative or loco-regional options | Reponse to treatment, OS | |
SKYSCRAPER-14 (NCT05904886) | 2026 | Atezolizumab + Bevacizumab with or without Tiragolumab | PD-L1 + TIGIT | Locally advanced or metastatic HCC, Child A | PFS | |
Second line or more (advanced stage) | ||||||
IMbrave251 (NCT04770896) | 2025 | Atezolizumab + standard of care (Sorafenib or Lenvatinib) vs standard of care alone | PD-L1 + multikinase | Previously treated with Atezolizumab and Bevacizumab, Child A/B7 | OS | |
