**3. Targeted therapies**

The vascular nature of HCC and that vascular endothelial growth factor (VEGF) play role of HCC development and metastasis, anti-angiogenesis agents have been studies extensively in the setting of advanced HCC. All, this knowledge dramatically leaded changing of systemic therapies form chemotherapy to molecular targeted agent. Since sorafenib was established as standard first line therapy in advanced HCC.

#### **3.1 Targeted first line therapies**

#### *3.1.1 Sorafenib*

Sorafenib, a multi-tyrosine kinase inhibitor with antiangiogenic effects is thought to be mediated by the blockade of VEGFR 2–3, platelet-derived growth factor receptor (PDGFR)-B, and other receptor tyrosine kinases. Sorafenib was approved in 2007 by the FDA as first-line therapy for unresectable HCC with BCLC stage C,

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

Child-Pugh class A or BCLC stage B that progressing after locoregional therapy. It was recommended in patient with well performance status (Eastern cooperative oncology group or ECOG PS 0–2) and preserve liver function test. The efficacy of this drug was demonstrated in two phase III, randomized, placebo-controlled clinical trials: the SHARP study [9] and the Asia-Pacific study (ORIENTAL) [10]. The patient population was mainly recruited form Europe and North America in SHARP study and Asian population in Asia-Pacific study. In the SHARP phase III studies, Sorafenib treatment with dose 400 mg twice a day compared to placebo. Among 602 patients, sorafenib significantly improved overall survival compared with placebo (HR 0.69; 10.7 mons vs. 7.9 mons, *P* < 0.001), DCR (disease control rate) about 43% in sorafenib arm compared to 32% in placebo arm (*P* = 0.002). Sorafenib study arm had significantly prolong time to radiologic progression in 5.5 mons compared with 2.8 mons in placebo arm (*P* < 0.001), Even though sorafenib prolong time to radiologic progression but there is no significant difference in term of time to symptomatic progression. Population of this trial was mostly patients with advanced stage HCC including 35% with macrovascular invasion and 50% with extrahepatic disease. The observed side effects were diarrhea, weight loss, hand-foot syndrome and hypophosphatemia. The result of the SHARP trial was subsequently confirmed in Asia-Pacific study and in 10 subsequent trials with and median overall survival in the range of 10–12 months. Efficacy of sorafenib was conducted in Asia-Pacific region population (The ORIENTAL study). The study was performed with the same design study to the SHARP trial. The Sorafenib arm group had significantly increase overall survival with 6.5 mons compared to 4.2 mons in placebo arm (*P* = 0.014). The overall survival-time and progression free survival time was lower compared to the SHARP study. Unfortunately, objective responses rate is poor with 2% by Response Evaluation Criteria in Solid Tumors (RECIST) and 10% by modified RECIST (mRECIST) [11] and no predictive biomarkers of responsiveness to sorafenib have been identified.

From the positively result, Sorafenib was approved with patient who has well Child-Pugh score (CTP A only); however, result for the GIDEON (Global investigation of therapeutic decision in Hepatocellular Carcinoma and its Treatment with Sorafenib) study, a large observational study assessing the safety profile and efficacy in patients with poor liver dysfunction, the result had a similar safety profile irrespective of Child-Pugh scoring [12]. However, Clinical practice guideline recommended that sorafenib in patient with underlying liver dysfunction is not recommended based on these data alone. The risks and benefits of sorafenib should be carefully consideration prior to start.

The recommended dose of sorafenib is 800 mg. Median treatment duration is estimated 5–6 months, but early recognition and prevention of toxicities can enhance tolerability. Sorafenib toxicities can be manageable. Common toxicities are diarrhea, hand-foot skin reaction (HFS), fatigue and hypertension. 35% of the patient in the study needed dose reduction and 15% of patients need to withdraw from the study due to adverse side effect sorafenib. Liver failure that related to sorafenib complications are marginal. Considering the restrictive indication of sorafenib in Child-Pugh A class only. However, because of its poor antitumor effect and relatively toxicity, developing a new targeted agent with superior efficacy and/or lower toxicity has been a critical issue.

#### *3.1.2 Lenvatinib*

After sorafenib has been approved for advanced HCC then several studies have been conducted to compare sorafenib in front line therapy such as sunitinib [13], brivatinib [14], erlotinib [15], linifanib [16] or everolimus [17] without

showing superiority (or at least non-inferiority) to sorafenib. Lenvatinib has only recently shown non-inferior clinical benefit in REFLECT study [18]. Lenvatinib is an oral multi-kinase inhibitor that targets VEGFR 1–3 and fibroblast growth factor receptor (FGFR) 1–4, among others. REFLECT study is an open-label, Phase III, multicenter, non-inferiority study demonstrated efficacy in Lenvatinib compared with sorafenib in patients with advanced HCC (excluding main portal vein invasion, clear bile duct invasion and > 50% of tumor to total liver volume occupancy). Lenvatinib was adjusted to body weight of patient. The study was evaluated in the first line therapy. The study met the primary endpoint of noninferiority in overall survival (HR = 0.92, 13.6 mons, Lenvatinib compared 12.3 mons, sorafenib, 95% CI = 0.79–1.06). Secondary outcomes in PFS and time to progression were better for Lenvatinib. Overall response rate (ORR) by mRECIST had significant better response (24% versus 9.2% for sorafenib, *P* < 0.001). This drug has shown a higher response rate compared with other tyrosine kinase inhibitors (TKIs) and sorafenib. Most common adverse effects compared with sorafenib were as follows: hypertension (42% versus 30%), diarrhea (39% versus 45%) and HFS (27% versus 52%). These results, Lenvatinib was approved as an option in first line therapy for advanced HCC.

Arguing for a use of Lenvatinib when rapid tumor shrinkage is warranted. Further subgroup analyses showed that Asian populations, patients with hepatitis B infection and high serum AFP > 200 ng/mL demonstrated a particular benefit form treatment with Lenvatinib. Comparing in term of side effects Lenvatinib was associated with more frequent side effects than sorafenib but manageable. More important high side effects were hypertension and weight loss for Lenvatinib. Based on these documents, current clinical practice guidelines recommended both Lenvatinib and sorafenib as frontline therapy for unresectable or advance stage HCC that are not amendable to surgery or locoregional therapies [19].
