**2.2. Lenvatinib**

Treatment approaches for HCC depend on the stage and the hepatic function, and includes surgical therapies (liver transplantation, resection, and ablation) and nonsurgical therapies, which may be liver-directed (percutaneous ethanol injection, radiofrequency ablation, trans-

Until 2008, there was no effective systemic therapy for advanced HCC. Cytotoxic chemotherapy has not been used routinely as of low efficacy and poor functional status for patients with advanced HCC, who often have cirrhosis. Since the advent of sorafenib in 2008, there has been a surge of several targeted and immune therapies with various degree of effectiveness. In this chapter, systemic therapies for advanced HCC will be reviewed. Those include oral kinase inhibitors, antiangiogenic monoclonal antibodies, immune-therapeutic approaches

Sorafenib is a multi-kinase inhibitor of vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptor (PDGFR) and Raf family kinases [2]. Sorafenib has shown to improve overall survival in comparison to placebo in advanced HCC, and it was the first drug to get Food and Drug Administration (FDA) approval as a first-line treatment for Child-Pugh score-A HCC. In the multicenter European SHARP trial, 602 inoperable HCC and Child-Turcotte-Pugh-A cirrhosis patients, were assigned to sorafenib (400 mg twice daily) or placebo [3]. The primary endpoint of the trial was overall survival, which was significantly longer in the sorafenib-treated group (10.7 vs. 7.9 months). Time to radiologic progression

Sorafenib was well tolerated in this trial. Diarrhea and hand-foot skin reaction were the only grade 3 or 4 adverse effects that occurred significantly more often in the treated group; (8 vs. 2%) and (8 vs. <1%) respectively. There were no differences in liver dysfunction or bleeding. An exploratory analysis of SHARP trial showed that hepatitis C related HCC has the highest median overall survival advantage of 6.6 months (14 vs. 7.4 months). This is in comparison to 3.6 months (9.7 vs. 6.1 months) in those with HBV related cirrhosis and 2.3 months (10.3 vs.

Hepatitis B virus is more prevalent in the Asian patients than in the Western population. Sorafenib was tested as a first-line treatment in Asian patients in a placebo-controlled phase III trial in which 226 patients with Child-Turcotte-Pugh A cirrhosis received sorafenib 400 mg twice daily or placebo [5]. Patients receiving sorafenib had significantly higher median overall

Based on the results of SHARP trial, the FDA approved sorafenib monotherapy as first-line

It is worth mentioning that the patients enrolled in the above trials had mostly Child-Turcotte-Pugh A cirrhosis. This is not representative of the real practice where a significant number of

survival (6.5 vs. 4.2 months). Grade 3 or 4 side effects were similar to SHARP trial.

was also longer (5.5 vs. 2.8 months). Objective response rates were low at 2%.

8 months) in those with alcohol-related liver disease [4].

therapy for unresectable HCC.

arterial embolization, external beam radiation therapy) or systemic therapies.

and cytotoxic chemotherapies.

**2. Kinase inhibitors**

**2.1. Sorafenib**

160 Liver Cancer

Lenvatinib is a multi-kinase inhibitor of VEGFRs, fibroblast growth factor receptors (FGFR), (PDGFR), c-Kit, and the RET proto-oncogene [10].

A randomized noninferiority trial, the REFLECT study, compared lenvatinib (12 mg once daily for body weight ≥60 kg, 8 mg daily for <60 kg) with sorafenib (400 mg daily for all patients) in 954 patients with unresectable HCC and no prior systemic therapy (99% Child-Turcotte-Pugh A) [11]. The predefined noninferiority margin (primary endpoint overall survival) was 1.08. Lenvatinib was noninferior to sorafenib (median overall survival 13.6 vs. 12.3 months, hazard ratio 0.92, 95% CI 0.79–1.06), the objective response rate was higher (24 vs. 9%), and median time to progression was longer (7.4 vs. 3.7 months, hazard ratio 0.66, 95% CI 0.57–0.77). Lenvatinib leads to higher grade 3 or 4 hypertension (23 vs. 14%), while sorafenib was associated with higher hand-foot skin reaction (11 vs. 3%).

Lenvatinib was approved in Japan in March 2018 for unresectable HCC. Lenvatinib is not approved by FDA yet.

Both sorafenib and lenvatinib can be used in the first-line treatment of advanced HCC. There are no data on second-line treatment after lenvatinib and whether lenvatinib is effective as a second line after sorafenib.
