**3.1. Bevacizumab**

**2.3. Regorafenib**

162 Liver Cancer

group.

**2.4. Cabozantinib**

**2.5. Axitinib**

**2.6. Sunitinib**

(FLT3) [17].

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].

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

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

In April 2017, the FDA expanded the indications for regorafenib to include patients with HCC

Regorafenib is an alternative to nivolumab for second-line HCC treatment. There are no trials

Cabozantinib is another inhibitor of several receptor tyrosine kinases, including the hepatocyte growth factor/c-MET and VEGFR [14]. Efficacy in patients with previously treated advanced HCC was shown in the placebo-controlled phase III CELESTIAL trial [15]. In a preliminary report, in the group of patients receiving second- or third-line treatment, median overall survival was significantly better with cabozantinib (10.2 vs. 8.0 months), and the difference was more pronounced when the analysis was limited to patients whose only prior therapy was sorafenib (median overall survival 11.3 vs. 7.2 months). The most common grade 3 or 4 adverse events with cabozantinib were palmar-plantar erythrodysesthesia (17 vs. 0 in the placebo group), hypertension (16 vs. 0%), increased aspartate aminotransferase (12 vs.

Axitinib is a selective kinase inhibitor that inhibits VEGFR. Axitinib was not superior to best supportive care alone in a randomized phase II trial comparing best supportive care plus axitinib (starting dose 5 mg twice daily) with placebo in 202 patients with advanced HCC who progressed on or were intolerant of one prior antiangiogenic therapy [16]. The difference in median overall survival (the primary endpoint), was not statistically significant (12.7 vs. 9.7).

Sunitinib is another orally active multi-kinase inhibitor that targets a variety of tyrosine kinases in addition to VEGFR, including PDGFRs, KIT, RET, and FMS-like tyrosine kinase 3

death 0.63) and disease control (objective response plus stable disease; 65 vs. 36%).

who had been previously treated with sorafenib.

7%), fatigue (10 vs. 4%), and diarrhea (10 vs. 2%).

comparing regorafenib with nivolumab in this setting.

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

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 randomized trials.

### **3.2. Ramucirumab**

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 patients with AFP-elevated HCC is ongoing.
