A substantial proportion of patients with hepatocellular carcinoma have to face up, sooner or later, to systemic therapy. The current standards as first line systemic therapies are either atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF), or durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4). However, the median overall survival remains below 20 months, and a minority of patients become long-term survivors. Of interest in immune-oncology strategies for hepatocellular carcinoma, the objective response seems to be the most reliable surrogate marker of better overall survival.
TRIPLET-HCC (NCT05665348) is a multicentre, randomised, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination by the addition of ipilimumab (anti-CTLA-4) to atezolizumab/bevacizumab, versus the double atezolizumab/bevacizumab combination. The main inclusion criteria are histologically proven BCLC-B/C HCC without previous systemic therapy. The primary objective of the phase II is the objective response rate in the triple arm, and OS in the triple versus double arms in the phase III. Secondary endpoints common to the phases II and III are the comparisons of progression-free survival, objective response rates, tolerance and quality of life. In addition, genetic and epigenetic studies from tissue and circulating DNA/RNA will be conducted to assess their prognostic or predictive value.
Abbreviations:CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), DCR (disease control rate), DOR (duration of response), DSMB (data safety monitoring board), EHS (extra-hepatic spread), HCC (hepatocellular carcinoma), IO (immuno-oncology), ICI (immune-checkpoint inhibitors), irAE (immune-related adverse event), MIV (macrovascular invasion), mITT (modified intention-to-treat), ORR (objective response rate), OS (overall survival), PFS (progression-free survival), PD-L1 (Programmed death-ligand 1), PD-1 (Programmed cell Death protein 1), TKI (tyrosine kinase inhibitor), TTR (time to response), TTP (time to progression), TRAE (treatment-related adverse event), VEGF (Vascular Endothelial Growth Factor)
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Digestive and Liver Disease
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424
- A global view of hepatocellular carcinoma: trends, risk, prevention and management.Nat Rev Gastroenterol Hepatol. 2019; 16: 589-604
- Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.Lancet Gastroenterol Hepatol. 2019; 4: 454-465
- High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial.Hepatology. 2002; 36: 1221-1226
- Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390
- Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 389: 56-66
- Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med. 2018; 379: 54-63
- Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet. 2018; 391: 1163-1173
- Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol. 2022; 23: 77-90
- Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial.J Clin Oncol. 2020; 38: 193-202
- Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts.Mol Cancer Ther. 2009; 8: 1761-1771
- VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.J Exp Med. 2015; 212: 139-148
- Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med. 2020; 20: 1894-1905
- Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma.J Hepatol. 2022; 4: 862-873
- Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study.Lancet Oncol. 2020; 21: 808-820
Abou-Alfa G.K., Chan S.L., Kudo M., et al. Phase-3 randomized, open-label, multicenter study of tremelimumab and durvalumab as first line therapy in patients with unresectable hepatocellular carcinoma: HIMALAYA. ASCO-GI 2022, San Francisco, Abstract #GI22
- Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer.J Exp Clin Cancer Res. 2021; 40: 184
- Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib the CheckMate 040 randomized clinical trial.JAMA Oncol. 2020; 11e204564
- Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the Phase IIIb/IV CheckMate 511 trial.J Clin Oncol. 2019; 11: 867-875
Published online: February 16, 2023
Accepted: January 27, 2023
Received: January 21, 2023
© 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.