Abstract: The only US Food and Drug Administration (FDA)-approved first-line systemic therapy for hepatocellular carcinoma (HCC) is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) and GEMOX (gemcitabine-oxaliplatin). Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib.

Keywords: liver cancer, chemotherapy, immunotherapy 

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Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in the US and around the world. The incidence of HCC is increasing, with an estimated 782,000 new cases per year worldwide.1In the US, where there are approximately 4 million people living with chronic infection of hepatitis C virus (HCV) and where the annual incidence rate of HCC among patients with HCV-related cirrhosis is 2%–8%, we can expect an increase in the annual incidence rate of HCC despite effective HCV treatment.2,3 In addition, recent data have shown that metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD), account for more number of cases of HCC than any other risk factor including HCV infection, which is primarily due to the high prevalence of NAFLD in the overall population.4 Sixty to seventy percent of the patients present with advanced disease which is not appropriate for surgical resection or liver-directed therapies.5 Therefore, for such patients, systemic therapy is highly recommended.6

The only US FDA-approved first-line systemic therapy for HCC is sorafenib, which is a multi-targeted oral small molecule tyrosine kinase inhibitor (TKI) that inhibits Raf kinase, the vascular endothelial growth factor receptors (VEGFRs) 1–3 and the platelet-derived growth factor receptor-β (PDGFR-β). Sorafenib was approved on the basis of results from the Phase III SHARP trial which demonstrated an overall survival (OS) benefit of sorafenib compared with best supportive care alone (10.7 months versus 7.9 months; hazard ratio [HR]=0.69; 95% confidence interval [CI]=0.55–0.87; P<0.001).7 The most common severe sorafenib-related toxicity was found to be diarrhea (grade 3 in 8% of the patients; grade 4 in <1% of the patients), hand–foot syndrome (grade 3 in 8% of the patients), and fatigue (grade 3 in 8% of the patients; grade 4 in 1% of the patients). Most frequent reasons for discontinuation of sorafenib were found to be gastrointestinal events (6%), fatigue (5%), and liver dysfunction (5%).7

Despite the observed survival benefit from sorafenib, resistance to sorafenib is very common. Primary resistance to sorafenib was identified in about a quarter of patients in the SHARP trial; however, 43% of the patients’ disease was found to be in control, which lasted for more days (≥28) beyond the first scan showing response or stable disease.7 Resistance to sorafenib is thought to be mediated by overexpression of epidermal growth factor receptor (EGFR) by the tumor including other downstream signaling molecules.8 Acquired resistance to sorafenib involves several mechanisms, such as abnormal activation of PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways to allow progression of malignant cells despite hypoxia, and epithelial–mesenchymal transition which enhances tumor cell migration and invasion.8

While many patients with sorafenib intolerance or resistance are unable to to receive additional therapy because of the advanced nature of their disease and cirrhosis, those with a good performance status often seek additional options. Because of comorbid cirrhosis and the general chemotherapy-refractory nature of HCC, finding second and third line treatment options can be challenging. Herein, we will describe systemic therapies that can be considered in patients with sorafenib refractory HCC. A summary of agents studied for use in HCC is provided in Table 1, with the most promising therapeutic options and their outcomes shown in Table 2.