Review Article

New Therapeutic Interventions for Advanced Hepatocellular Carcinoma

Saroja Bangaru; Jorge A. Marrero; Amit G. Singal


Aliment Pharmacol Ther. 2019;51(1):78-89. 

In This Article

Abstract and Introduction


Background: Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first-line and second-line treatment options should yield significant improvements in survival.

Aim: To summarize the evolving landscape of treatment options for patients with advanced HCC.

Methods: We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences.

Results: Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine-kinase inhibitor, was recently shown to have non-inferior survival vs sorafenib and is another first-line treatment option. The tyrosine-kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second-line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population.

Conclusion: There are several first-line and second-line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.


Hepatocellular carcinoma (HCC) is the sixth most common cancer world-wide and the third leading cause of cancer death, causing approximately 750 000 deaths annually.[1] Most cases of HCC occur in East Asia and Africa, driven by high rates of endemic hepatitis B in those areas. In the Western world, HCC primarily occurs in the setting of cirrhosis and is driven by an aging population with chronic hepatitis C and a growing prevalence of non-alcoholic fatty liver disease. While HCC incidence and mortality in the United States and Europe is lower than that East Asia, modeling studies project continued increases in incidence and HCC is expected to become the third leading cause of cancer death in the United States by 2030.[2]

Prognosis for HCC is largely driven by tumor stage at time of diagnosis, with 5-year survival exceeding 70% for early stage tumors compared to a median survival of only 1–2 years for those with intermediate to advanced stage tumors.[3] Although survival for early and intermediate stage HCC has improved over the past 15 years, prognosis for patients with advanced HCC has remained poor, with no significant improvement. An analysis of the SEER database suggested 5-year survival failed to improve between 2001–2007 and 2008–2013 for patients with vascular invasion (15.5% vs 15.3%, P = .37) or distant metastases (2.4% vs 2.9%, P = .10).[4] These differences in prognosis is largely driven by treatment efficacy across different stages of disease. Historically, the most common staging system for HCC has been the Barcelona Clinic Liver Cancer (BCLC) staging system, which classifies HCC into five stages—stage 0, A, B, C, and D—based on tumor burden, liver dysfunction, and patient performance status.[5] Curative treatments such as liver transplantation, surgical resection, or local ablative therapies are recommended for patients with early stage (BCLC 0 or A) HCC. Patients with intermediate stage (BCLC B) disease are typically treated with locoregional therapies such as transarterial chemoembolization (TACE) or radioembolization (TARE), although patients with significant intrahepatic tumor burden (eg BCLC subclasses B3 and B4) or progression after locoregional therapy may instead benefit from systemic therapy. Systemic therapy also continues to remain the primary treatment for patients with advanced (BCLC C) HCC, ie patients with vascular invasion, distant metastases or tumor-related symptoms (ECOG performance status 1–2).

Herein, we review phase II and phase III clinical trials of systemic therapies for patients with advanced HCC published in PubMed or presented at national conferences (Table 1). We focus on recent progress in the area of systemic therapy for advanced HCC, where the landscape has expanded from a single approved agent, sorafenib, to multiple potential therapies—both in the first-line and second-line settings.