Clin Mol Hepatol > Volume 29(2); 2023 > Article
Ahn, Tran, and Yang: Systemic therapy in advanced hepatocellular carcinoma
While advanced hepatocellular carcinoma (HCC) is an incurable disease, decades of research and clinical trials have led to substantial progress in treatment for advanced HCC [1]. In the 20th century, patients with advanced HCC were treated with conventional chemotherapy which offered little to no benefit with significant adverse effects [2]. The first breakthrough came with the molecularly targeted agents in the family of oral multi-tyrosine kinase inhibitors. In 2007, the multi-target kinase inhibitor sorafenib became the first-line systemic therapy for advanced HCC [3]. Since 2017, multiple positive phase III clinical trials have led to the approval of several additional molecularly targeted agents—lenvatinib [4] as a first-line, and regorafenib [5], cabozantinib [6], and ramucirumab [7] as second-line options. Additional multikinase inhibitors such as donafenib [8] and apatinib [9] have shown promising results in phase III trials conducted in China.
A dramatic therapeutic paradigm shift was driven by the advent of immune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). The first studied immunotherapy agents in HCC were the anti-PD-1 antibodies, nivolumab and pembrolizumab, which demonstrated clinical benefit and pembrolizumab has received accelerated approval as second-line agents following sorafenib [10,11]. More recently, tislelizumab (anti-PD-1 monoclonal antibody) demonstrated non-inferior overall survival (OS) compared to sorafenib (median OS: 15.9 months vs. 14.1 months; stratified hazard ratio [HR] 0.85 [95.003% CI 0.712–1.019]) in first-line setting phase 3 trial [12].
In 2020, the results of the landmark IMbrave 150 study led to the largest change in the treatment landscape of advanced HCC [13]. In this global phase III trial of patients with untreated unresectable HCC, the combination of atezolizumab (anti-PD-L1 antibody) and bevacizumab (anti-vascular endothelial growth factor antibody) was significantly superior to sorafenib with an improved median overall survival (19.2 months vs. 13.4 months, HR 0.58, 95% CI 0.42–0.79) and comparable rates of grade 3 or 4 adverse events (43% vs. 46%) [13,14]. This has quickly led to the adoption of atezolizumab-bevacizumab as the standard first-line systemic therapy [15-17].
Immunotherapy doublets have shown promising results [2]. The addition of an anti-CTLA-4 antibody to an anti-PD-1 or PD-L1 antibody significantly enhances the antitumor response by increasing the intratumoral concentration of T lymphocytes [18]. The combination of nivolumab and CTLA-4 inhibitor ipilimumab was approved as second-line therapy based on the CheckMate 040 study that showed manageable safety, promising response rate, and durable responses [19]. Recently, the phase III HIMALAYA trial showed positive results for durvalumab (anti-PD-L1 antibody) as a monotherapy and in combination with tremelimumab (anti-CTLA-4 antibody) for first-line treatment of advanced HCC [20]. In this study, durvalumab monotherapy was non-inferior to sorafenib, and moreover the durvalumab-tremelimumab combination was superior to sorafenib (overall survival: 16.4 vs. 13.8 months) [20]. Based on the results of the HIMALAYA trial, durvalumab-tremelimumab combination recently obtained US Food and Drug Administration (FDA) approval as a firstline treatment for advanced HCC. Therefore, the durvalumabtremelimumab combination offers another promising firstline treatment especially among those who cannot receive bevacizumab due to its anti-angiogenic effects.
Combinations of immunotherapy with molecularly targeted agents have mixed results. In the phase III COSMIC-312 trial, combination of atezolizumab with cabozantinib significantly improved progression-free survival compared to sorafenib (HR 0.63, 95% CI 0.44–0.91), while it did not reach statistical significance for overall survival (HR 0.90, 95% CI 0.69–1.18) [21]. Similarly, treatment with pembrolizumab and lenvatinib appeared to result in some improvement in overall survival and progression-free survival compared with lenvatinib monotherapy, but it did not meet statistical significance [22]. In the phase III ORIENT-32 trial, the combination of sintilimab (anti-PD-1 antibody) and IBI305 (bevacizumab biosimilar) showed significantly improved overall survival and progression-free survival compared to sorafenib in an exclusively Chinese patient cohort with high proportion of hepatitis B infection [23]. In another phase III trial reported in 2022 (NCT03764293), the combination of camrelizumab (anti-PD-1 antibody) and apatinib was again superior to sorafenib (HR 0.62, 95% CI 0.49–0.80) and provided a median overall survival of 22.1 months, the longest overall survival observed to date in phase III trials of advanced HCC [24].
More recently, synergistic treatment efficacy of the combined locoregional treatment and immunotherapy have been reported and several phase 2 and 3 clinical trials are ongoing to determine the efficacy and safety of combined immunotherapy and locoregional treatment [25,26]. A phase III study comparing sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib showed that compared to sorafenib alone, SBRT prior to sorafenib improved overall survival (HR 0.72, 95% CI 0.52–0.99), progression-free survival (HR 0.55, 95% CI 0.40–0.75), and time to progression (HR 0.69, 95% CI 0.48–0.99) with improved quality of life [27].
We are in an exciting era where the landscape of systemic therapy for advanced HCC is rapidly evolving. Additional firstand second-line regimens are expected to be available as we await the readouts of ongoing phase III trials investigating different combinations of immunotherapy, molecularly targeted agents with, and without concurrent locoregional treatment. As responses to systemic therapy can be highly heterogeneous, there is an unmet need for biomarkers that would predict treatment response and enable an individualized approach to therapy.


Authors’ contributions
Ju Dong Yang devised the project and the main conceptual ideas for the snapshot; Joseph C. Ahn conducted the literature search and identified relevant studies to be included in the review; Ahn JC drafted the manuscript and the figure; Ju Dong Yang and Nguyen H. Tran revised the manuscript critically for important intellectual content; and all authors approved the final version to be published.
Conflicts of Interest
Dr. Yang provides a consulting service for Exact Sciences and Gilead. Dr. Yang’s research is funded by National Institute of Health 1K08CA259534-01A1. Dr. Tran’s research is funded by National Institute of Health 1K23MD017217-01A1.



hepatocellular carcinoma
programmed cell death protein-1
programmed death-ligand 1
cytotoxic T lymphocyte-associated protein 4
hazard ratio
overall survival
stereotactic body radiation therapy


1. Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ 2020;371:m3544.
crossref pmid
2. Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022 Nov 11. doi: 10.1038/s41575-022-00704-9.
crossref pmid pdf
3. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
crossref pmid
4. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. 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.
crossref pmid
5. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al.; RESORCE Investigators. 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 Erratum in: Lancet 2017;389:36.
crossref pmid
6. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 2018;379:54-63.
crossref pmid pmc
7. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al.; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:282-296.
crossref pmid
8. Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallelcontrolled phase II-III trial. J Clin Oncol 2021;39:3002-3011.
9. Qin S, Li Q, Gu S, Chen X, Lin L, Wang Z, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2021;6:559-568.
10. El-Khoueiry AB, Melero I, Yau TC, Crocenzi TS, Kudo M, Hsu C, et al. Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040. J Clin Oncol 2018;36(4 suppl):475.
11. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al.; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018;19:940-952 Erratum in: Lancet Oncol 2018;19:e440.
12. Qin S, Kudo M, Meyer T, Finn RS, Vogel A, Bai Y, et al. Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Ann Oncol 2022;33(Suppl 7):S1402-S1403.

13. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al.; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
14. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022;76:862-873.
crossref pmid
15. Gordan JD, Kennedy EB, Abou-Alfa GK, Beg MS, Brower ST, Gade TP, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol 2020;38:4317-4345.
crossref pmid
16. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, GarciaCriado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-693.
crossref pmid pmc
17. Llovet JM, Villanueva A, Marrero JA, Schwartz M, Meyer T, Galle PR, et al.; AASLD Panel of experts on trial design in HCC. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology 2021;73 Suppl 1:158-191.
crossref pmid pdf
18. Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 2005;175:7746-7754.
crossref pmid pmc pdf
19. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. 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;6:e204564 Erratum in: JAMA Oncol 2021;7:140.
crossref pmid pmc
20. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence 2022;1:EVIDoa2100070.
21. Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, openlabel, randomised, phase 3 trial. Lancet Oncol 2022;23:995-1008.
crossref pmid
22. Finn MK R.S, Merle P, Meyer T, Qin S, Ikeda M, Xu R, et al. Pembrolizumab/lenvatinib combo misses survival end points in unresectable HCC. Ann Oncol 2022;33(Suppl 7):S1808-S869.

23. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al.; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol 2021;22:977-990 Erratum in: Lancet Oncol 2021;22:e347.
crossref pmid
24. Qin S, Chan LS, Gu S, Bai Y, Ren Z, Lin X, et al. Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A randomized, phase III trial. Ann Oncol 2022;33(Suppl 7):S1401-S1402.

25. Llovet JM, Vogel A, Madoff DC, Finn RS, Ogasawara S, Ren Z, et al. Randomized phase 3 LEAP-012 study: transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment. Cardiovasc Intervent Radiol 2022;45:405-412.
crossref pmid pmc pdf
26. Tai D, Loke K, Gogna A, Kaya NA, Tan SH, Hennedige T, et al. Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial. Lancet Gastroenterol Hepatol 2021;6:1025-1035.
crossref pmid
27. Dawson LA, Winter K, Knox J, Zhu AX, Krishnan S, Guha C, et al. NRG/RTOG 1112: Randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). J Clin Oncol 2023;41(4 suppl):489.

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