Originally published as JCO Early Release 10.1200/JCO.2008.19.7996 on November 24 2008

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Sorafenib in Hepatocellular Carcinoma: Separating the Hype From the Hope

University of California at San Francisco, San Francisco, CA

Although there are many cancers that have defied the promise of new therapies, hepatocellular carcinoma (HCC) has long been perceived as a particularly challenging disease, a third rail of drug development: touch it and your drug is dead. This presumably represents the usual duality of problems and competing causes of death for patients with HCC—a lethal, invasive cancer and compromised hepatic function from the underlying liver disease that spawns the cancer.

HCC presents other obstacles as well. Response rate, the conventional go/no-go decision maker from phase II trials, is an unreliable surrogate for HCC because of the inelasticity of the cirrhotic liver and the failure of tumor death to lead to lesion shrinkage, even when substantial tumor necrosis occurs. HCC also poses the challenge of intrinsic resistance to chemotherapy drugs as a result of increased expression of multidrug resistance transporters and active intracellular metabolism.^1-3 Impaired liver function brings into question the proper dosing of medications (compared with phase I studies in patients with normal organ function) and complicates the interpretation of toxicities. Furthermore, given the wide range of primary ablative and embolization techniques used for unresectable HCC, it is typically only the far advanced patient with HCC who is referred for systemic therapy.

For all of these reasons, no systemic treatment until now has been demonstrated to confer a survival advantage for patients with HCC in a randomized clinical trial. This has changed with the report and now publication of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), a study comparing sorafenib with placebo in patients with HCC.⁴

The multikinase inhibitor sorafenib is a bi-aryl urea that targets the serine-threonine kinase Raf-1 and has antiangiogenic activity.^5-7 Preclinical studies show that Raf-1 kinase signaling along with prolific tumor angiogenesis together play an important role in the evolution of HCC, lending a molecular rationale for the use of sorafenib in this malignancy.^6,8-11 In the phase I setting, sorafenib demonstrated an acceptable safety profile as well as the observation of a partial response in a patient with HCC.¹² The phase II trial of sorafenib in advanced HCC, published by Abou-Alfa et al in 2006,¹³ demonstrated minimal toxicity but also little in the way of conventional Response Evaluation Criteria in Solid Tumors (RECIST) responses. Many tumors seemed to have necrosis, however, including some with apparent size increase by conventional imaging. Survival parameters were comparable to those of the best published combinations of systemic chemotherapy in advanced HCC.^13-15 What followed was the international, multicenter, randomized, double-blind, placebo-controlled, phase III SHARP trial.⁴

The SHARP trial enrolled 602 patients with advanced HCC and preserved liver function. The population comprised approximately 30% of patients with hepatitis C virus (HCV) infection, 20% with hepatitis B virus (HBV) infection, and 25% with alcoholic liver disease. Nearly all patients had Child-Pugh class A (CPA) cirrhosis, with Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned to receive sorafenib at a starting dose of 400 mg twice daily versus placebo. The primary end points were overall survival (OS) and time to symptomatic progression, and patients could remain on treatment until they experienced disease progression both radiographically and symptomatically. At the second planned interim analysis, OS was significantly longer in the sorafenib group compared with placebo, with OS of 10.7 months versus 7.9 months, respectively, and hazard ratio for sorafenib of 0.69 (P < .001). There was no difference in time to symptomatic progression, though time to radiologic progression was significantly longer in the sorafenib group. Only nine RECIST responses were seen in the entire patient population. Disease control rate (a composite of complete response, partial response, and stable disease) was significantly higher in the sorafenib group (43% v 32%; P = .002).

This study offers the first hope for life prolongation for the more than 600,000 patients who die each year from HCC worldwide.¹⁶ Approximately 80% of these cases occur in developing countries with limited resources.^16,17 Reminiscent of the HIV epidemic, the potential difference in availability of sorafenib for patients with advanced HCC again offers a harsh reminder of the disparities in health care between the first and third worlds.¹⁷

Leaving aside the challenges of access to drug, however, the question remains unanswered whether sorafenib will prove an efficacious and appropriate therapy for the majority of patients with HCC. With the first hope of an active therapy in a grim disease, there is a natural tendency toward expansiveness—the hype. Returning to the basics, one must remember to ask "Do the data from this trial apply to the patient in my office?"

There are several key differences between the patients in the SHARP trial and the majority of patients with advanced HCC. Foremost among these differences is the relative proportion of viral hepatitides. In the SHARP study, HCV was the cause of liver disease in approximately 30% of patients, and HBV in approximately 20%.⁴ In contrast, more than 70% of patients with HCC in the United States and western Europe test positive for HCV.¹⁸ Worldwide, HBV infection accounts for 60% to 80% of HCC cases and ranks second only to tobacco as a human carcinogen.¹⁹

To be fair, the SHARP trial was not designed to assess the efficacy and safety of sorafenib specific to the etiology of liver disease, so inferences rely on evaluating subgroups and comparison across trials. Analysis of the 178 patients with HCV-associated HCC in the SHARP trial showed OS of 14.0 months with sorafenib therapy versus 7.9 months with placebo, a trend toward superior outcomes by comparison with the SHARP population as a whole.²⁰ Additional subgroup analysis in patients with alcohol-related HCC showed similar outcomes to the overall population.²¹

Given the dominance of HBV as the cause of HCC worldwide, the relative scarcity of such patients in the SHARP trial does not allow an assessment of the efficacy of sorafenib in HBV and makes a subset analysis less statistically informative. Acknowledging the limited sample size, however, the patients with HBV in SHARP seemed to have similar survival outcomes as the rest of the randomly assigned population (J. Germino, Bayer, personal communication, August 2008). Corroborating but different results were seen in the Asian randomized phase III trial of sorafenib versus placebo in patients with advanced HCC, in which more than 70% of the 226 patients were positive for HBV.²² Comparing sorafenib versus placebo in these patients, OS was 6.2 months with sorafenib versus 4.1 months in the placebo group, with hazard ratio for sorafenib of 0.67 (P = .0155). Although this benefit is of the same relative magnitude as was seen with sorafenib in the SHARP trial, the patients in both arms do appreciably worse than those of SHARP.

It is unclear what factors account for the differential outcomes between the Asian patients and the Westernized SHARP population. The Asian patients had poorer performance status, more prior therapies, more severe liver disease despite CPA status, and potentially increased exposure to other factors influencing hepatocarcinogenesis, such as aflatoxin. The subgroup analysis of the HBV population in SHARP suggests, but does not confirm, that HBV is not responsible. Molecular studies show significant heterogeneity among liver cancers, which may reflect the etiology of underlying liver disease, potentially influencing response to therapy.²³ Recently, sophisticated genetic analyses of HCC tumor tissue have identified underlying differences between HCV- and HBV-associated liver cancers.^24,25 It is also interesting to note that HCV core protein activates Raf-1 signaling, which may influence sensitivity to a Raf-1 inhibitor such as sorafenib.^13,26,27 Cumulatively, these points raise the possibility that liver cancers associated with HBV, HCV, and other etiologies of underlying liver injury have different natural histories and could exhibit different responses to a molecularly targeted therapy.

It is important for the clinician to note that the SHARP patient population further diverges from the majority of patients with HCC by the limited extent of underlying liver dysfunction. As noted, 97% of the study population was classified as CPA. This element of the trial design enriched the study's ability to detect clinical benefit by minimizing the confounding variable of death from progressive liver disease.⁴ By definition, therefore, this trial does not address the safety or efficacy of sorafenib in patients with greater degrees of liver compromise. The phase II study by Abou-Alfa et al¹³ included 28% of patients with Child-Pugh class B (CPB), and although the pharmacokinetic profiles between groups were similar, OS was 14 weeks in CPB patients compared with 41 weeks in CPA patients.^13,28 Furthermore, more hyperbilirubinemia, encephalopathy, and ascites developed in the CPB subgroup, raising concern for hepatic decompensation from sorafenib, although these likely represented independent sequelae of progressive, underlying liver disease. In a study of sorafenib in 58 poor-risk patients, including 26% with CPB or worse liver function and 50% with portal vein thrombosis, overall response rate (including stable disease) was 20%, but 34% of patients experienced grade 3 or 4 toxicity.²⁹

These small studies suggest the potential for significant toxicity and less clinical benefit from sorafenib in patients with compromised hepatic function. As an index of the percentage of patients with HCC who have such hepatic dysfunction, the Carcinoma of the Liver Italian Programme-01 trial evaluated response to tamoxifen in 496 patients with HCC of all stages, and greater than 50% of patients enrolled in the study had CPB or worse liver function at baseline.³⁰ Although global population data are lacking and Carcinoma of the Liver Italian Programme-01 is just one study, these data suggest that patients with HCC with preserved liver function comprise the minority, particularly with the evolution of newer interventional and surgical ablation techniques that delay the introduction of systemic therapies. This does not discredit selectivity in clinical trials for HCC, however, as it heightens sensitivity to detect a clinical difference between treatment arms. Such selectivity was observed in the landmark trial establishing survival benefit with chemoembolization in unresectable HCC, in that 903 patients were screened to identify 112 patients meeting entry criteria.³¹ The highly selected population enabled detection of a statistically significant improvement in survival in patients with unresectable disease treated with chemoembolization by comparison with arterial embolization and control arms. Nonetheless, the findings apply only to that limited group.

On the basis of the SHARP data, sorafenib was approved by the US Food and Drug Administration (FDA) for first-line use in advanced HCC in November 2007. Despite the specifics of the patient population studied, the FDA approval is not limited to CPA patients but applies to any patients with advanced HCC. In contrast, the National Comprehensive Cancer Network practice guidelines for patients with advanced HCC are more stringent, assessing the data as inadequate to define dosing or safety in patients with CPB or worse liver function and advising extreme caution in patients with elevated bilirubin. As a cancer drug with an FDA label more permissive than the algorithm of the National Comprehensive Cancer Network, sorafenib is an exception to the rule.

In sum, the SHARP results can at this point only be applied to a minority of patients with advanced HCC. Nonetheless, sorafenib offers real hope of efficacious treatment for patients with advanced HCC and preserved liver function. Prospective clinical trial data evaluating the safety and activity of sorafenib in patients with compromised liver function would be ideal, although data from the soon-to-be-launched Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib registry may provide a clearer profile of risk and benefit in patients treated with sorafenib outside of the clinical trial setting.

The activity of sorafenib in advanced disease also opens the doors for studies in patients who will have or have already undergone resection, ablation, chemoembolization, or liver transplantation. A chemoembolization with or without sorafenib trial under the auspices of the Eastern Cooperative Oncology Group will soon be open to accrual, and Bayer-Onyx will conduct an adjuvant trial in patients undergoing radiofrequency ablation or resection. Neoadjuvant treatment with sorafenib could improve resection outcomes and increase surgical candidacy, although the absence of tumor shrinkage makes this less likely. Sorafenib also offers the possibility of bridging therapy for patients with HCC awaiting transplantation.

In advanced disease, a recent randomized, phase II study suggests improved outcomes with the addition of sorafenib to doxorubicin.³² The Cancer and Leukemia Group B will compare this combination with the benchmark of sorafenib monotherapy in a randomized, phase III trial. Bayer/Onyx are also planning a trial to compare sorafenib monotherapy with the combination of sorafenib and erlotinib. A new era of research in liver cancer has dawned!

The survival improvement despite the paucity of traditional responses seen in the SHARP trial will influence future clinical trial design in HCC, as well. RECIST criteria have failed to predict the clinical activity of sorafenib, although the phase II study by Abou-Alfa et al¹³ in 2006 showed tumor necrosis in many patients. A phase II study of sunitinib in unresectable HCC also showed significant tumor necrosis in 46% of treated patients, with excellent correlation with digital contrast-enhanced imaging, despite the absence of corresponding RECIST responses.³³ These limitations of RECIST in HCC are mirrored by the imatinib in the gastrointestinal stromal tumors (GIST) story, where the extremely effective imatinib therapy is often underestimated by RECIST.^34-36 The Choi response criteria are an example of parameters developed to better characterize imatinib response in GIST.^37,38 These criteria combine tumor density (a measure of tumor necrosis) as well as the conventional measurement of size, classifying a tumor response as either a 10% decrease in size or a 15% decrease in tumor density on contrast-enhanced computed tomography. In a study of 58 patients with GIST treated with imatinib, the Choi criteria correlated more closely and reproducibly with the end points of time to progression and disease-specific survival than RECIST.³⁷ A retrospective, radiographic analysis of SHARP comparing survival outcomes with degree of tumor necrosis could guide further research to optimize response measures in this disease.

The success of sorafenib encourages us to proceed with other targeted therapies and their combinations in HCC, as well as to search for biomarkers predictive of response. In the Abou-Alfa et al¹³ study, tumors with higher levels of extracellular regulated kinase (pERK) expression by immunohistochemistry were associated with a significantly longer time to progression (P = .00034), suggesting that pERK expression may be a biomarker of tumor response to Raf-1 inhibition by sorafenib. A similar analysis from the SHARP trial comparing survival outcomes and tumor pERK status for patients with available tumor tissue could provide a valuable correlate to this data. As noted above, sunitinib has also demonstrated modest activity in HCC, leading to a Pfizer-supported head-to-head comparison of sorafenib and sunitinib.^33,39-41 There is some evidence that biomarkers of antiangiogenic effect and tyrosine kinase inhibition may be correlated with tumor response.^39,41 These early results may inform the molecular and imaging correlative studies in future large, randomized trials in HCC.

In conclusion, further study is required to better define which subsets of patients will benefit from sorafenib. Safety and efficacy data are insufficient at present in patients with compromised liver function beyond CPA, and it remains unclear whether Asian patients or patients with HBV infection benefit equally to patients in the Western hemisphere, where HCV infection is more common. Increasing understanding of the heterogeneous molecular profiles of liver cancer may identify new targets of therapy in this complex disease.

The flurry of activity surrounding sorafenib is an exciting development. The National Cancer Institute will sponsor a State of the Science meeting on hepatocellular carcinoma in December 2008, and there will be much to discuss. Although there has been some hype associated with sorafenib, it has ushered in an era of hope for patients with HCC.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Alan P. Venook, Amgen Inc, Genentech, Novartis, Pfizer Inc, GlaxoSmithKline, Bristol-Myers Squibb Co Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Alan P. Venook

Manuscript writing: Robin K. Kelley, Alan P. Venook

Final approval of manuscript: Robin K. Kelley, Alan P. Venook

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kelley, R. K. Articles by Venook, A. P. Search for Related Content PubMed PubMed Citation Articles by Kelley, R. K. Articles by Venook, A. P. Social Bookmarking                            What's this?