**3.2 Targeted second-line therapies**

In the SHARP/ASIAN-Pacific and REFLECT studies, it was shown that administration of TKIs only leads to relatively short periods of tumor control. The recent data evaluated the efficacy of targeted therapies in second-line therapy that shown clinical benefit in patients with advanced HCC that progressed on prior sorafenib therapy in front-line treatment, drugs that considered in this setting was regorafenib, carbozantinib and ramucirumab.

#### *3.2.1 Regorafenib*

Regorafenib, a multi-kinase inhibitor targeting similar kinases as sorafenib. Phase III study (RESOUCE) study [20] was conducted to comparing regorafenib with placebo in advanced HCC patients progressing despite sorafenib. The starting dose of regorafenib is 160 mg/day (3 weeks on and 1 week off). The primary endpoint of this study is overall survival. The study was positive for its primary end points (HR = 0.62, P < 0.001, 10.6 months in the regorafenib group vs. 7.8 months in the placebo). The secondary endpoints were PFS, ORR and safety profile. Regorafenib had significantly prolonged time to disease progression (3.1 versus 1.5 months). The efficacy of treatment improved survival in all subgroups of patients. Population in this trial, 88% were BCLC stage C and 12% were BCLC stage B, with all of them tolerant to sorafenib but progression on treatment. 70% of patients had extrahepatic spread and 30% had macrovascular invasion. Around half of patients has high AFP more than 400 ng/dL. The response rate was only 10%, based on mRECIST. Median time on treatment was 3.5 months. Hypertension was the most common adverse

#### *Systemic Therapy in Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.100257*

effect, occurring in 15% of patients on regorafenib, followed by HFS. Adverse effects led to 51% dose reductions and 10% treatment discontinuation. Sequential administration of sorafenib and regorafenib resulted in an OS of 26 months compared with 19 months in patients receiving only sorafenib as first-line and placebo as second line treatment [21].

Regorafenib is the standard of care for patients with advanced HCC who have tolerated sorafenib but progressed and recommended in patients with well-preserved liver function test (Child-Pugh A class) and good ECOG PS 0–1.
