Which questions remain unanswered following the successful development of sorafenib in hepatocellular carcinoma?

In patients with advanced hepatocellular carcinoma who have a good performance status and Child—Turcotte—Pugh class A liver function, sorafenib represents a new standard of care.

» Keith Flaherty and Weijing Sun

Summary
 
Investigation of the effects of various antiangiogenic agents in the therapy of solid tumours has been a dominant theme in oncology for the past decade. Hepatocellular carcinoma has joined the short list of tumour types for which single-agent antiangiogenic therapy has shown clear clinical benefit. Here we discuss the findings of a multicentre, phase III trial by Llovet et al. (Sorafenib in advanced hepatocelluar carcinoma.NEngl JMed 359:378–390), which compared overall survival, time to symptomatic progression and time to radiologic progression in patients with hepatocellular carcinoma who received either sorafenib or placebo. Patients treated with sorafenib had approximately three months longer overall survival and time to radiologic progression than patients who received placebo. Elucidation of tumour-specific and patient-specific factors that identify which patients with hepatocellular carcinoma will derive greatest benefit from antiangiogenic therapies such as sorafenib is of critical importance.

Hepatocellular carcinoma (HCC) is one of the world's major health problems, with 500,000 new cases diagnosed per year worldwide and a rising incidence in the US and Europe. The challenge in treatment of advanced disease is two fold: lack of effective agents and limited treatment efficacy owing to the underlying liver dysfunction. Preclinical data demonstrate that antiangiogenic agents, including sorafenib and bevacizumab, have efficacy in HCC cell lines and xenograft models. [1]

Sorafenib targets a wide spectrum of kinases that are active in disease pathways, including c-Raf, VEGF and platelet-derived growth factor beta PDGF |3). The primary mechanism of action of sorafenib has been difficult to discern in some tumour types during clinical trials of this drug. Sorafenib inhibits tumour angiogenesis in human tumour xenografts, although the specific target or targets involved cannot be conclusively stated. 

Two critical observations have been made on the HCC trials conducted with sorafenib. Bevacizumab, a monoclonal antibody that exclusively targets VEGF, was evaluated in several phase II trials alone and in combination with chemotherapy in HCC. While no phase III data have yet demonstrated a survival benefit with bevacizumab in HCC, the phase II trials suggest that such a benefit exists. [2-4] These data support the hypothesis that the inhibition of VEGF signaling achieved with sorafenib might contribute significantly to its activity in HCC. On the other hand, Abou-Alfa and colleagues noted a correlation between high tumour MAP kinase (MAPK) pathway activity and prolonged progression-free survival in response to sorafenib. [5] As this study lacked a control group, a definitive conclusion is not possible that activation of this pathway represents a useful predictor of response; however, the available evidence suggests that high MAPK activity is an adverse prognostic feature. Thus, the association between high MAPK pathway activity and good clinical outcome in patients with high intrinsic MAPK activity who responded well to sorafenib suggests that the drug exerts some effect on this pathway, presumably at the level of Raf. Therefore, sorafenib might exert an influence on both VEGF-mediated angiogenesis and MAPK pathway activity in the context of HCC. 

The regulatory authorities in the US and Europe approved sorafenib for the treatment of advanced HCC on the basis of data from a large, randomised, double-blind, placebo-controlled, phase III study (SHARP). [6] The study included 602 patients with advanced HCC from 121 centres in 21 countries in Europe, North America, South America and Australia who were ineligible for, or who experienced disease progression after, surgical or locoregional therapies. Other key inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, Child— Turcotte—Pugh class A liver function, life expectancy more than 12 weeks and adequate haematologic, liver and renal function. Patients who had received molecularly targeted or other systemic therapies were excluded. After randomisation, patients were given either 400 mg sorafenib twice daily (n=299) or a matching placebo (n=303). The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (HR 0.69, range 0.55—0.87; P<0.001). Notably, most patients had a good performance status and preserved liver function, which is not usually seen in general oncology practice: 54% of patients had an ECOG performance status of 0, 38% had an ECOG performance status of 1, and 95% of patients had Child—Turcotte—Pugh class A liver function. Data are lacking for patients with relatively advanced liver failure (Child—Turcotte—Pugh class B or C) and poor performance status (ECOG score >2). Since the SHARP trial population was predominantly European and only a small proportion had hepatitis B virus as the causative factor, a second phase III study was conducted to verify the role of sorafenib in Asian patients with HCC, among whom hepatitis B viral infection is the predominant causative factor of advanced disease (75%). [7] The benefits of sorafenib mirrored those in the SHARP trial with respect to the survival advantage (HR 0.67, range 0.49—0.93; P=0.0155), but both groups had inferior outcomes compared with SHARP trial participants (median overall survival 6.5 months and 4.1 months for the sorafenib and placebo groups, respectively). Although the Asian cohort had more advanced disease, these results suggest that sorafenib might offer greater benefit in hepatitis C virus- infected patients than in other aetiologic subgroups of HCC, an observation that deserves further investigation. Another provocative result comes from a phase II, randomised study that showed potential benefit for the combination of sorafenib and doxorubicin compared with doxorubicin alone (median overall survival 13.8 months vs 6.5 months; P=0.0129). [8] These results, however, must be interpreted carefully as the sample size was small and the combination therapy was associated with increased cardiac toxicity (left ventricular dysfunction 19% vs 2%). 

After a decade's efforts, sorafenib is the first agent to demonstrate a survival benefit in the treatment of advanced HCC. The primary mechanism of action of this agent remains uncertain, but inhibition of both angiogenesis and the MAPK pathway seem to have a role. An improved clinical effect might be obtained byusing combinations of drugs that target angiogenesis and MAPK signaling, and this strategy could form the next generation of trials that combine sorafenib with other targeted therapies. Caution should be applied when sorafenib is considered for patients with HCC and advanced liver failure. Such patients were not included in the phase II or phase III trials and they might not tolerate sorafenib as well as those with preserved liver function. More studies are needed in this population of patients.

Article references:

1. Liu L et al. (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res66: 11851–11858

2. Schwartz JD et al.(2006) Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein [abstract]. J Clin Oncol24: (Suppl): S213

3. Zhu AX et al. (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol24: 1898–1903

4. Sun W et al. (2007) Combination of capecitabine, oxaliplatin and bevacizumab in treatment of advanced hepatocellular carcinoma: a phase II study [abstract]. J Clin Oncol25: (Suppl): S240

5. Abou-Alfa GK et al. (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol24: 4293–4300

6. Llovet JM et al. (2008) Sorafenib in advanced hepatocelluar carcinoma. N Engl J Med359: 378–390

7. Cheng A et al. (2008) Randomized phase III trial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma [abstract]. J Clin Oncol26: 4509

8. Abou-Alfa GK et al. (2008) Final results from a phase II, randomized, double-blind study of sorafenib plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma.[abstract #128]

Competing interests: Keith Flaherty declared associations with Bayer and Onyx Pharmaceuticals. See the article online at www.nature/clinicalpractice for full details of the relationship