Advancing hepatocellular carcinoma treatment: a triple combination for patients with extrahepatic metastasis—better or bust?

Liver cancer is the 6^th most diagnosed cancer, with approximately 865,000 new cases reported in 2022. Liver cancer caused 757,948 deaths making it the 3^rd leading cause of cancer-related death, worldwide (1,2). Hepatocellular carcinoma (HCC) accounts for more than two-thirds of cases of primary liver cancer (1). The Barcelona Clinic Liver Cancer (BCLC) staging system stratifies patients based on the extent of their cancer, the degree of liver dysfunction, and their performance status as well as provides guidance to stage-based treatment (3). BCLC stage C includes patients with locally advanced HCC and patients with extrahepatic spread with preserved liver function; with systemic therapy being the recommended treatment approach for this patient group. Extrahepatic metastasis occurs in about 30% of patients with HCC. The prognosis of these patients is poor with a median survival time between 4% and 5% (4,5). The most frequent sites of extrahepatic spread include lungs, regional lymph nodes, bones, and adrenal glands (4). Traditional treatment modalities fall short in managing patients with extrahepatic metastasis, highlighting an urgent need for pioneering therapeutic strategies (2).

The LTSC study by He and colleagues (6): (I) reports results of a phase 2 trial of a triple combination for patients with HCC with extrahepatic metastasis; and (II) provides exploratory analyses of single-nucleus RNA sequencing (snRNA-seq) profiles of HCC tissue to assess the clinical benefits of provided treatment.

In 2005, sorafenib was approved as first-line therapy for advanced HCC by the Food and Drug Administration (FDA). Sorafenib blocks HCC cell proliferation, the vascular endothelial growth factor (VEGF) receptors, and the platelet-derived growth factor receptor-β (PDGFR-β) leading to a 3-month survival benefit compared to placebo (7). Yet, for decades this drug remained the only targeted therapy for advanced HCC. The race was on to improve the outcome of systemic therapy for patients with this deadly cancer. Many clinical trials have failed to surpass the overall survival (OS) of sorafenib highlighting the complexity of HCC targeted therapy. After levantinib was approved by the FDA as a new first-line treatment for advanced HCC showing a small but significant additional 1.3 months improved median OS compared with sorafenib (8,9), the race took off. Next in line were immune checkpoint inhibitors (ICIs), especially anti-programmed death receptor-1 (PD-1) and anti-programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs) which have drawn attention from scientists leading to many pioneering trials investigating their efficacy in advanced HCC. The IMbrave150 study combining a PD-L1 antibody (atezolizumab) and a VEGF antibody (bevacizumab) finally showed a significant step-up in success with an improved OS (19.2 vs. 13.4 months) and progression-free survival (PFS) (6.8 vs. 4.3 months) compared with the sorafenib group (10). Finally, in 2020, 15 years after the approval of sorafenib, a new standard of care for advanced HCC became available. Regorafenib became available as a second-line treatment for patients with advanced HCC who had progressive disease on sorafenib (9,11) and cabozantinib was approved as a second-line treatment for patients with advanced HCC (9,12,13).

Despite these improvements in the outcome of patients with advanced HCC, OS rates and PFS rates are still unsatisfactory. The race continued by combining different HCC treatment strategies. Transarterial chemoembolization (TACE) recommended for intermediate stage (BCLC stage B) (3), a group of patients with multinodular disease, preserved liver function, and excellent performance status is now being trialed in combination with systemic therapy for advanced HCC (BCLC stage C). It remains however uncertain if combining TACE with systemic agents with activity against VEGF will improve outcomes based on presumptive synergistic action. One meta-analysis proved that concept by showing that TACE, lenvatinib, and PD-1 inhibitors significantly improved OS, PFS, objective response rate (ORR), and disease control rate in advanced HCC (14). A phase II clinical trial of the combination of TACE with traditional chemotherapy (FOLFOX—oxaliplatin, 5-fluorouracil, and leucovorin), lenvatinib, and a PD-1 antibody—toripalimab—concluded that this approach provides safe and encouraging antitumor activity for advanced HCC (15). However, TACE is a liver only locoregional therapy, and the role of TACE in patients with extrahepatic metastasis is uncertain (16). Perhaps, a triple combination of systemic chemotherapy, TKIs, and ICIs could be a new and exciting strategy for advanced HCC with extrahepatic metastasis.

Completed and current studies in patients with advanced HCC do not discriminate between patients with locally advanced stages or extrahepatic spread as all these patients are classified as BCLC stage C patients.

He et al. entered uncharted territory by conducting an exploratory study solely in patients with extrahepatic spread. This single-arm phase II trial (LTSC study) evaluated the benefits of combining lenvatinib, toripalimab, and FOLFOX chemotherapy in advanced HCC with extrahepatic metastasis. Thirty patients without previous treatment were included in this study and received six cycles of intra-arterial chemotherapy, with each cycle consisting of a 21-day triple combination treatment. The study showed an impressive 6-month PFS rate of 66.7%, with a median PFS of 9.73 months, a median OS of 14.63 months, and an ORR of 43.3%; thus likely underscoring the potential of this triple regimen to improve clinical outcomes (6). In comparison, the IMbrave150 trial reported improved outcomes with atezolizumab/bevacizumab in a general cohort of HCC patients, its effectiveness in those with extrahepatic metastasis and high-risk features was less pronounced (17). The LTSC study demonstrates promising survival and response data of this triple combination therapy suggesting synergetic antitumor activity of the agents with an acceptable safety profile in patients with extrahepatic metastasis.

Biomarkers and liquid biopsy are playing an increasing role in pre-treatment clinical decision-making and different biomarkers for HCC are being explored. The CheckMate 040 trial identified four inflammatory gene signatures as potential predictors of response to nivolumab (18). A phase I/II study indicated an early increase of peripheral CD8⁺ T cells associated with better response to durvalumab and tremelimumab (19). For patients receiving atezolizumab/bevacizumab combination, pre-existing immunity, such as high expression of CD274, T-effector signature, and intratumoral CD8⁺ T cell density, high expression of VEGFR2, regulatory T cell, and myeloid inflammation signatures were associated with better outcomes with the combination therapy (20,21). He and colleagues also provided an exploratory analysis of snRNA-seq profiles of HCC biopsy samples as part of their study. They showed that patients with a higher presence of tumor-infiltrating immune cells were more likely to benefit from this combination therapy. Tumors compromising of two specific subtypes of hepatocytes—AKR1C2⁺ and CFHR4⁺ malignant hepatocytes—benefited less from this triple regimen (6).

In summary, He et al. report the first study of a triple combo therapy in patients with HCC with extrahepatic spread and show exciting results in OS, PFS, and an impressive ORR of 43.3%. As this is a small sample size, single-arm design, without a control group receiving standard care, monotherapy, or dual combination therapy, the specific contribution of each component in the triple combination regimen remains less defined and needs further validation. Future prospective, ideally multicenter studies should compare different treatment combination strategies—locoregional intervention, combinations of different targeted agents including immunotherapy, and traditional chemotherapy. International multicenter participation will allow for an assessment of the different treatment strategies in different patient populations. The LTSC study population was predominantly hepatitis B virus (HBV)-related HCC (29 of 30 participants), but previous preclinical and clinical data suggest that non-viral HCC and, particularly, metabolic dysfunction associated steatotic liver disease-related HCC, might be less responsive to immunotherapy, and therefore limits the generalizability of the findings of the LTSC study (21,22). Additionally, all the participants are Asian and from the same demographic area, which may not reflect the broader global population of HCC patients with extrahepatic metastasis.

He and colleagues are adding additional biomarkers to the worldwide catalog of liquid biopsy which will broaden our knowledge in predicting response or failure of certain cancer therapies. The race will continue until we reach the finish line and identify the most suitable therapy for every single HCC patient.

The exploration of triple therapy with lenvatinib, toripalimab, and FOLFOX chemotherapy/intra-arterial infusion in patients with HCC with extrahepatic metastasis by He et al. adds more urgently needed data to define better treatment options for a patient population with a poor prognosis. While surely promising, the results call for cautious optimism, underscoring the need for further research to address the study’s limitations and to validate these findings in broader clinical settings. Through such endeavors, the oncology community continues to push the boundaries of advanced HCC treatment.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-66/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-66/coif). C.X. has served as an unpaid member of the University of South Dakota MD Admission Committee, an unpaid editorial board member of Clinical and Experimental Gastroenterology, and an unpaid academic board member of Journal of Pancreatology. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
3. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-93. [Crossref] [PubMed]
4. Kummar S, Shafi NQ. Metastatic hepatocellular carcinoma. Clin Oncol (R Coll Radiol) 2003;15:288-94. [Crossref] [PubMed]
5. Uka K, Aikata H, Takaki S, et al. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 2007;13:414-20. [Crossref] [PubMed]
6. He M, Huang Y, Du Z, et al. Lenvatinib, Toripalimab plus FOLFOX Chemotherapy in Hepatocellular Carcinoma Patients with Extrahepatic Metastasis: A Biomolecular Exploratory, Phase II Trial (LTSC). Clin Cancer Res 2023;29:5104-15. [Crossref] [PubMed]
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. [Crossref] [PubMed]
8. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-73. [Crossref] [PubMed]
9. Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma. Lancet 2022;400:1345-62. [Crossref] [PubMed]
10. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
11. Bruix J, Qin S, Merle P, et al. 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. [Crossref] [PubMed]
12. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 2018;379:54-63. [Crossref] [PubMed]
13. Freemantle N, Mollon P, Meyer T, et al. Quality of life assessment of cabozantinib in patients with advanced hepatocellular carcinoma in the CELESTIAL trial. Eur J Cancer 2022;168:91-8. [Crossref] [PubMed]
14. Wang L, Lin L, Zhou W. Efficacy and safety of transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor in the treatment of advanced hepatocellular carcinoma: A meta-analysis. Pharmacol Ther 2024;257:108634. [Crossref] [PubMed]
15. Lai Z, He M, Bu X, et al. Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: A biomolecular exploratory, phase II trial. Eur J Cancer 2022;174:68-77. [Crossref] [PubMed]
16. Lyu N, Kong Y, Pan T, et al. Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin in Hepatocellular Cancer with Extrahepatic Spread. J Vasc Interv Radiol 2019;30:349-357.e2. [PubMed]
17. Mbrave I. 150: Exploratory Efficacy and Safety Results in Patients With Hepatocellular Carcinoma Without Macrovascular Invasion or Extrahepatic Spread Treated With Atezolizumab + Bevacizumab or Sorafenib. Gastroenterol Hepatol (N Y) 2021;17:14-5.
18. Sangro B, Melero I, Wadhawan S, et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol 2020;73:1460-9. [Crossref] [PubMed]
19. Kelley RK, Sangro B, Harris W, et al. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. J Clin Oncol 2021;39:2991-3001. [Crossref] [PubMed]
20. Zhu AX, Abbas AR, de Galarreta MR, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med 2022;28:1599-611. [Crossref] [PubMed]
21. Rimassa L, Finn RS, Sangro B. Combination immunotherapy for hepatocellular carcinoma. J Hepatol 2023;79:506-15. [Crossref] [PubMed]
22. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450-6. [Crossref] [PubMed]