Hepatocellular carcinoma (HCC) continues to be one of the major causes of cancer mortality in Hong Kong. The heterogeneity of HCC results in a great diversity of clinical presentation and tumor biology, which poses a significant challenge to disease management. At the 22nd Hong Kong Medical Forum, Professor Thomas Yau, Clinical Associate Professor of the Department of Medicine, the University of Hong Kong, shared his insights into the management of advanced HCC.
HCC is the fourth commonest cancer and the third lethal cancer in Hong Kong.1 In western countries, hepatitis C virus (HCV) infection as well as alcohol-related cirrhosis and possibly nonalcoholic fatty liver disease are the main attributable factors of HCC.2 In contrast, the high incidence of HCC is associated with endemic hepatitis B virus (HBV) infection in most Asian regions, including Hong Kong.2 Patients with HBV-associated HCC generally have better preserved liver function when compared with those with HCV-associated HCC.2 As the different geographic etiologies of HCC may impact treatment response, there is no universal staging system nor treatment guideline for HCC. Potentially, the curative treatments of HCC are mostly surgical in nature and only few medical interventions have been thoroughly tested in HCC.3 Effective treatment options for those who are not amenable to surgical resection or local treatment are limited.
The Barcelona Clinic Liver Cancer (BCLC) staging system
Several classification systems are available for HCC. The BCLC staging system which links stage stratification with a recommended treatment strategy is widely used (Figure 1).3 Although the BCLC staging system has been endorsed by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines and has been externally validated in European and American patient cohorts, it may not be reflective of cancer progression or prognosis in Hong Kong HCC patients for whom HBV infection is the predominant etiologic factor.2
It is noteworthy that the BCLC staging classification was developed mainly based on the prognostic analysis of cohorts of predominantly HCV-infected patients.2 In addition, the BCLC classification was first developed in 1999 with conservative surgical treatment recommendations.2 Recent advances in surgical treatments and local ablative procedures are not taken into consideration in the BCLC classification.2 Indeed, studies have shown that the performance of BCLC staging system might be better in Caucasian patients and early stage diseases only.2
The Hong Kong Liver Cancer (HKLC) staging system
The HKLC classification (Figure 2) was developed by a group of Hong Kong experts to provide treatment guidance for Asian patients with HCC.2 This system was derived from the results of a large cohort study of 3,856 HCC patients who were predominantly infected with HBV.2 Eastern Cooperative Oncology Group (ECOG) performance status (PS), Child-Pugh grade, liver tumor status, and the presence of extrahepatic vascular invasion or metastasis were included in this system.2 The HKLC treatment guidelines expand the criteria for potential curative therapies.2 Patients with slightly hampered physical function status, large or multiple tumors, or even intrahepatic venous invasion were recommended for curative therapies.2 Such patients are classified as the intermediate stage (B) or the advanced stage (C) according to the BCLC staging system and would be considered only for noncurative options, such as transcatheter arterial chemoembolization (TACE) or systemic treatment.2,3
In the study of a cohort of 3,856 HCC patients, the HKLC staging system was shown to be more prognostic than the BCLC system for Asian HCC patients who were predominantly infected with HBV.2 More importantly, the HKLC staging system improved survival outcomes by recommending more aggressive treatments for the subsets of BCLC intermediate- and advanced-stage patients (Figure 3).2 The study findings also showed hepatic resection in a properly selected advanced subgroup of HCC patients might derive substantial survival benefits and TACE might offer survival benefits for some of the BCLC-C/HKLC-III patients.2
Unmet need in patients with advanced or unresectable HCC
There are few available treatment options for patients with advanced or unresectable HCC. Low response rates and failure of extending survival were typically reported in clinical studies evaluating the use of conventional cytotoxic chemotherapies for the treatment of advanced HCC.4-6 Sorafenib, an oral multi-kinase inhibitor that suppresses tumor cell proliferation and angiogenesis, has been evaluated in a phase II and two phase III trials for the treatment of advanced or metastatic HCC.5,7,8 Two phase III randomized trials conducted in Western and Asian populations demonstrated consistent survival benefit with sorafenib monotherapy, which led to regulatory approval for the use of sorafenib in advanced HCC.4,7,9 Nonetheless, the survival benefit associated with sorafenib was generally modest and its use is generally limited to those with good hepatic reserves.4,7,9 Although regorafenib, another multi-kinase inhibitor, has been reported to provide an overall survival benefit compared with placebo in selected patients who tolerated sorafenib, but progressed, while on therapy, effective therapies for patients with unresectable HCC are still insufficient.10
c-MET inhibitor: Novel HCC treatment
The cellular-mesenchymal-epithelial transition (c-MET) factor receptor has gained much interest in recent drug development for HCC. MET is a transmembrane receptor tyrosine kinase (RTK) that is widely expressed in the epithelial and endothelial cells.11 MET has been implicated as a mediator of many aspects of tumor pathobiology, including tumor survival, proliferation, angiogenesis, invasion, and dissemination.9,11 Encouraging phase II data on c-MET inhibitors, including tivantinib, cabozantinib and foretinib, in HCC have been reported.9,11
Foretinib is an oral multi-kinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2.9 In a phase I/II single-arm study evaluating the safety, pharmacokinetics, pharmacodynamics and activity of foretinib, Asian patients with advanced HCC were dose escalated on foretinib (30–60 mg) every day using the standard 3+3 design in the phase I part.9 Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety.9 Promising antitumor activity and good tolerability of foretinib as the first-line therapy were observed in this phase I/II study.9 The MTD of foretinib in Asian patients with advanced HCC was established as 30 mg/day.9 Thirty-five patients treated with 30 mg foretinib were evaluable for efficacy using modified Response Evaluation Criteria in Solid Tumors (mRECIST) [Figure 4].9 The overall objective response rate (ORR), median duration of response (DoR) and the median overall survival (OS) were 22.9% (95% CI: 10.4-40.1), 7.6 months (95% CI: 5.32-not available) and 15.7 months (95% CI: 7.9-not available), respectively.9
PD-1 inhibitor: Immuno-oncology agent for the treatment of advanced HCC
HCC has been shown to be immunogenic.12 The presence of tumor-infiltrating lymphocytes expressing programmed cell death protein-1 (PD-1) in HCC lesions and their correlation with clinical outcomes suggest that immunotherapy may be useful in this setting.13
Nivolumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody that disrupts PD-1 immune checkpoint signaling, restoring the antitumor activity of otherwise suppressed effector T cells. 13
In the CheckMate 040 trial, an on-going phase 1/2, open-label, non-comparative, dose escalation and expansion trial, patients received intravenous nivolumab 0.1–10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design) and nivolumab 3 mg/kg every 2 weeks in the dose-expansion phase in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected.13 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase).13 During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability.13 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events.13 The ORR (investigator-assessed) was 20% (95% CI: 15-26) in the dose expansion phase with a median DoR of 9.9 months; disease control rate (DCR) was 64% (95% CI: 58-71) (Table 1).13 The 6-month OS rate was 83% (95% CI: 78–88) and the 9-month OS rate was 74% (95% CI: 67–79) with nivolumab 3 mg/kg in patients in the dose-expansion phase [Table 1].13
HCC remains a challenging disease to treat. A better staging and treatment algorithm for Asian HCC patients, the HKLC staging system, may lead to better clinical outcomes. Despite the modest survival benefit and significant toxicities associated with sorafenib, sorafenib has been the standard of care for patients with advanced HCC. At present, treatment options for HCC patients intolerant of or progressing on sorafenib are limited. Encouraging data on c-MET inhibitors and PD-1 inhibitor suggest additional therapeutic options may soon be available for patients with advanced HCC.
1. Hong Kong Cancer Registry, Hospital Authority, 2014 (Accessed 19th May 2017, at http://www3haorghk/cancereg/toptenhtml)
2. Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014;146:1691-700.e3.
3. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma. JNCI: Journal of the National Cancer Institute 2008;100:698-711.
4. Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. Journal of the National Cancer Institute 2005;97:1532-8.
5. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. The New England journal of medicine 2008;359:378-90.
6. Thomas MB, O’Beirne JP, Furuse J, Chan AT, Abou-Alfa G, Johnson P. Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy. Annals of surgical oncology 2008;15:1008-14.
7. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. The Lancet Oncology 2009;10:25-34.
8. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology 2006;24:4293-300.
9. Yau TCC, Lencioni R, Sukeepaisarnjaroen W, et al. A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma. Clinical Cancer Research 2017;23:2405-13.
10. 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. The Lancet;389:56-66.
11. Lee J, Chan J, Choo S. Clinical Development of c-MET Inhibition in Hepatocellular Carcinoma. Diseases 2015;3:306.
12. Breous E, Thimme R. Potential of immunotherapy for hepatocellular carcinoma. Journal of Hepatology;54:830-4.
13. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet.