**2.3. Regorafenib**

Regorafenib is an antiangiogenic (including VEGFR-1, VEGFR-2, and VEGFR-3), anti-stromal, and an oncogenic tyrosine kinase inhibitor that is structurally similar to sorafenib [12].

Sunitinib was significantly inferior to sorafenib in a phase III trial that directly compared both drugs in 1073 previously untreated patients with advanced HCC [18]. The trial was closed prematurely when an interim analysis revealed that patients receiving sunitinib had significantly worse survival (median 7.9 vs. 10.2 months) and more frequent and severe treatment-

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Bevacizumab is a monoclonal antibody directed against VEGFR that has some activity in advanced HCC. Efficacy was shown in a trial in which 46 patients with advanced nonmetastatic HCC received single-agent bevacizumab at a dose of either 5 or 10 mg/kg once every other week [19]. An objective response was documented in six (13%, one complete), and the median progression-free survival was 6.9 months. The most common grade 3 or 4 toxicities

Bevacizumab is also active in combination with capecitabine, with or without oxaliplatin [20, 21], and gemcitabine combined with oxaliplatin (GEMOX) [22]. Whether any of those combination regimens are better than bevacizumab alone is not clear and will require ran-

Ramucirumab is a recombinant monoclonal antibody that binds to VEGFR-2. The REACH trial failed to show a significant survival advantage relative to placebo (median overall survival 9.2 vs. 7.6 months) in patients with advanced HCC who progressed on sorafenib [23]. An unplanned group analysis suggested a possible survival benefit in patients with a high initial level of alpha-fetoprotein (AFP) above 400 ng/mL) at diagnosis. A follow-up phase III trial in

Immune-based approaches that focus on vaccination strategies, cytokines or non-specific T cell activation have been tested for many years in HCC without promising result. However, the recent advancement in immune-oncology with the FDA approval of many immune checkpoint inhibitors, sparked a great interest in the immune-based treatment approaches for patients with HCC. The strategy of adopting an immunocentric approach to HCC treatment may be potentially more efficacious and less toxic. Interestingly, what makes the immunotherapy appealing in liver cancer is that HCC is a high immunogenic cancer, due to high blood flow with unique vast tumor antigen repertoire because of mutations and aberrant expression profiles [24]. On the other hand, there is an inherently immunosuppressive microenvironment

related toxicity.

**3.1. Bevacizumab**

domized trials.

**3.2. Ramucirumab**

**4.1. Introduction**

patients with AFP-elevated HCC is ongoing.

**4. Immunotherapeutic approaches**

**3. Antiangiogenic monoclonal antibodies**

were hypertension (15%), thrombosis (6%), and major bleeding (11%).

In the randomized RESORCE trial, 573 patients who received sorafenib for at least 20 days at a dose of at least 400 mg daily and who had radiologic progression were randomly assigned to regorafenib (160 mg once daily for 3 weeks on and 1 week off) or placebo [13]. Regorafenib was associated with significantly higher median OS (10.6 vs. 7.8 months, hazard ratio for death 0.63) and disease control (objective response plus stable disease; 65 vs. 36%).

Treatment was relatively well tolerated; grade 3 or 4 hypertension, hand-foot skin disease and fatigue were more frequent with regorafenib. Sixty-eight percent of patients treated with regorafenib required dose modification for adverse events compared with 31% of the placebo group.

In April 2017, the FDA expanded the indications for regorafenib to include patients with HCC who had been previously treated with sorafenib.

Regorafenib is an alternative to nivolumab for second-line HCC treatment. There are no trials comparing regorafenib with nivolumab in this setting.
