Hepatocellular Carcinoma, Novel Therapies on the Horizon

Imane El Dika; Iman Makki; Ghassan K. Abou-Alfa


Chin Clin Oncol. 2021;10(1):12 

In This Article

Abstract and Introduction


Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with high mortality rate. Incidence remains high due to the persistent prevalence of viral hepatitis, alcoholic cirrhosis, and non-alcoholic fatty liver disease (NFLD). Despite screening efforts, the majority of patients present with advanced disease, add to the high risk of recurrence after curative surgery. Conventional chemotherapy did not alter the nature history of advanced and metastatic HCC. The discovery of multiple tyrosine kinase inhibitors (TKIs) led to the approval of sorafenib as first efficacious therapy. A new era in the treatment paradigm of HCC is evolving. Since the advent of sorafenib as an active treatment option for patients presenting with advanced or metastatic disease, several agents have been examined. This was linked with many failures, and success stories to celebrate. Herein, we describe the historical progress and current advances of systemic therapies post-sorafenib. Lenvatinib, regorafenib, cabozantinib, ramucirumab, pembrolizumab, and nivolumab, are all presently added and available therapeutic options in the advanced setting. The evaluation of novel treatment combinations including anti-angiogenic, TKIs plus checkpoint inhibitors, add to dual checkpoint inhibitors is evolving rapidly starting with the advent of the combination of atezolizumab plus bevacizumab. Combining local and systemic therapies is being actively investigated, as an option for locally advanced disease conventionally treated with locoregional approaches. The horizon remains promising and continues to evolve for HCC a disease long considered with unmet needs.


Primary liver cancer has become the second cause of cancer related mortality globally, with hepatocellular carcinoma (HCC) accounting for 90% of primary liver cancers.[1,2] HCC with a high incidence in Asia, and Africa,[3,4] is now on the rise in Europe and the United States likely secondary to the increase in hepatitis C and non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NFLD/NASH).[5–8] Early stage HCC can potentially be cured through surgical resection, ablation, or liver transplantation; however, recurrence rates remain high and survival remains low.[9–13] The majority of patients are diagnosed at a later more advanced stage that lacks any curative options.[14] Historically, systemic therapy had failed to show any mortality benefit in advanced HCC patients until sorafenib was approved by the United States Food and Drug Administration (FDA)[15] followed by approval worldwide. Several agents demonstrated clinical activity since. Tyrosine kinase inhibitors (TKIs) showed survival benefit with tolerable side effects, yet limited improvement in prognosis and HCC remains an area of unmet need.[2] In the TKI era, overall survival in patients with advanced HCC was averaging around ten months,[16] highlighting the importance of further effort. Experimenting with checkpoint inhibitors alone and in combination with other modalities and novel therapeutic targets followed. Herein, we will review current systemic therapies and expand upon some of the relevant ongoing trials and future horizons.