Multi-targeted kinase inhibitors represent one of the most important new classes of agents introduced for the treatment of HCC. Of these, sorafenib was the first to gain approval from the FDA. Sorafenib targets both tumor cell proliferation and angiogenesis pathways, and for these reasons, it was thought it could be useful in patients with HCC. Sorafenib was subsequently investigated in clinical trials (), and promising efficacy results led to its evaluation in 2 phase III trials.
Data from Llovet JM, et al. N Engl J Med. 2008;359: 378-390
The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial was a multicenter, 2-arm, double-blind phase III clinical study that compared a standard dose of sorafenib (400 mg twice daily) administered orally versus placebo.7
It was a large trial, which randomized 602 patients with measurable, unresectable, advanced HCC in a 1:1 ratio. Patients continued to receive therapy until observation of both radiologic and symptomatic effects, unacceptable adverse events, or death. The baseline characteristics were well balanced between the 2 treatment groups. Most of the study subjects were men (87% of patients in each arm). The majority of patients were European, and the etiology of liver disease was distributed among hepatitis B virus, hepatitis C virus, and alcohol-induced liver disease.
Patients in the sorafenib group experienced a significantly longer OS (1 of 2 primary endpoints) compared with the placebo group (10.7 vs 7.9 months, hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55–0.87; P<.001). The 1-year rate of OS was also higher among patients who received sorafenib compared with placebo (44% vs 33%). The 4-month progression-free survival was 62% among patients who received sorafenib and 42% in the placebo group. However, the improvement in the second primary endpoint, median time to symptomatic progression, did not reach statistical significance. In contrast, the secondary endpoint, time to radiologic progression, was significantly longer among patients who received sorafenib therapy (5.5 vs 2.8 months, HR, 0.58; 95% CI, 0.45–0.74; P<.001). Sorafenib patients also experienced a significantly improved disease control rate, which was primarily due to a higher incidence of stable disease, as the rate of response was relatively modest (the overall response was only 2.3% among sorafenib-treated patients).
Overall, sorafenib was generally well-tolerated, although drug-related adverse events did occur at a higher frequency in the treatment group compared with placebo (80% vs 52%); most of these were grade 1 or 2 in severity. Grade 3 adverse events that occurred significantly more in the sorafenib group compared with placebo included diarrhea (8% vs 2%; P
<.001), hand-foot skin reaction (8% vs <1%; P
<.001), and weight loss (2% vs 0%; P
=.03). More patients who received sorafenib had to undergo a dose reduction due to adverse events (26% vs 7%). Because of the potential for sorafenib-related adverse events, dose modification schedules and guidelines have been developed.8
Dose reduction strategies associated with sorafenib include both a delay in dose administration and a decrease in dosage. Cardiac toxicity, a particularly concerning adverse event associated with the use of tyrosine kinase inhibitors, was not a significant issue in this trial.
The second major phase III trial that evaluated sorafenib in HCC was the Asia-Pacific, a randomized, double-blind, placebo-controlled study.9
Compared with the SHARP study, this trial was smaller, randomizing a total of 226 patients with advanced HCC to receive either oral sorafenib (400 mg twice daily) or placebo. Randomization occurred in a 2:1 ratio. Enrolled patients were from China, South Korea, and Taiwan. Patients had not previously received systemic therapy, and all were categorized as Child-Pugh liver function class A. Due to the location of this trial, the hepatitis B virus accounted for the majority of disease etiology.
As in the SHARP trial, sorafenib was found to be significantly superior to placebo. Median OS was significantly prolonged among patients who received sorafenib compared with placebo (6.5 vs 4.2 months, HR, 0.68; 95% CI, 0.50–0.93; P=.014). Median time to progression was also improved with sorafenib (2.8 vs 1.4 months, HR, 0.57; 95% CI, 0.42–0.79; P=.0005). As was seen in other studies, sorafenib did not produce a significant response rate.
The safety profile of sorafenib was similar to that reported in the SHARP trial. Among 149 assessable patients, the most frequently reported grade 3 or 4 adverse events were hand-foot skin reaction, diarrhea, and fatigue; of these, hand-foot skin reaction and diarrhea were the most common causes of dose reduction.
Although the overall efficacy results of the Asia-Pacific study were similar to those in the SHARP trial, they were less robust. This difference may reflect the study population, which had more advanced disease.
To improve upon the efficacy associated with sorafenib, biomarkers with the potential to predict response to sorafenib have been investigated. One biomarker currently under investigation is the phosphorylated form of extracelluar signal-regulated kinase (p-ERK), which is a downstream molecule in the RAF/MEK/ERK signaling pathway, a target of sorafenib.10
Constitutive activation of this pathway leads to high levels of p-ERK, and possibly indicates that the tumor cell relies on this pathway for survival. Using immunohistochemistry, patients whose tumor cells had a greater staining intensity for p-ERK experienced a longer time to progression,11
which suggests an improved response to sorafenib, perhaps due to pathway inhibition. Other possible biomarkers under investigation to predict response to sorafenib include HGF and c-Kit. It is possible that these markers are related to OS in HCC patients.