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Originally published as JCO Early Release 10.1200/JCO.2005.01.3441 on August 14 2006 © 2006 American Society of Clinical Oncology. Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
From the Memorial Sloan-Kettering Cancer Center, New York, NY; Bayer Pharmaceuticals Corporation, West Haven, CT; Ospedale S. Chiara, Pisa; Ospedale Morgagni Pierantoni, Forli; Istituto Clinico Humanitas, Rozzano (MI); Bayer S.p.A. PH/Medical Department, Milan, Italy; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; AZ-VUB, Brussels, Belgium; and the Centre René Gauducheau, Nantes, France Address reprint requests to Ghassan K. Abou-Alfa, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10022; e-mail: abou-alg{at}mskcc.org
Purpose: This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients. Methods: Patients with inoperable HCC, no prior systemic treatment, and Child–Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients. Results: Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand–foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy. Conclusion: Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide,1 with approximately 500,000 new cases per year. Approximately 80% of cases arise in Asia and Africa,2 mainly due to chronic hepatitis B virus (HBV) infection. The incidence of HCC is rising in the United States and Europe because of increased incidence of hepatitis C (HCV) infection.3 Surgical resection and liver transplantation are considered the only cures for HCC, but benefit only approximately 15% of patients.4 Unresectable or metastatic disease patients have median survival of a few months.5 There is a substantial need for novel treatments for advanced HCC, because systemic therapy induces relatively few responses and has no clear survival benefit. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/extracellular signal regulated kinase (ERK) pathway has a role in HCC.6 Furthermore, over-expression of activated MEK1 in HCC cell lines enhanced tumor growth and survival by preventing apoptosis. HCV core proteins elicit high basal Raf-1 activity in hepatocytes, increasing the risk of neoplastic transformation.7,8 HCC tumors are highly vascularized, and vascular endothelial growth factor (VEGF) augments HCC development and metastasis.9 Therefore, blocking signaling through Raf-1 may offer therapeutic benefits in HCC.6 Sorafenib, an oral multikinase inhibitor, blocks tumor cell proliferation by targeting Raf/MEK/ERK signaling at the level of Raf kinase, and exerts an antiangiogenic effect by targeting vascular endothelial growth factor receptor-2/-3 (VEGFR-2/-3), and platelet derived growth factor receptor beta (PDGFR-β) tyrosine kinases.10 In a phase I trial of sorafenib, a confirmed partial response was observed in a metastatic HCC patient.11 This response, and the importance of VEGF and Raf/MEK/ERK signaling in HCC, prompted this phase II study to evaluate further the efficacy, toxicity, and pharmacokinetics (PK) of sorafenib in advanced HCC. The predictive value of molecular biomarkers in determining time to progression (TTP) was also evaluated.
This was a multicenter, international, uncontrolled phase II trial in advanced HCC patients. The trial was approved by a human investigation committee at each center, and conducted in accordance with the US Dept of Health and Human Services guidelines. Informed consent was obtained from each patient.
Patients' Eligibility Patients with tumors of mixed histology or fibrolamellar variant, pregnant or lactating women, or those requiring systemic anticancer therapy, biologic-response modifiers, or CYP34A inhibitors or with medical/psychological/social problems that might affect study participation or evaluations were excluded.
Treatment and Dose Modifications Dose delays or modifications were required for drug-related toxicities. For grade 3/4 toxicities; patients received lower doses when toxicity improved to grade 2 or better, but therapy was discontinued if recovery time was 3 weeks or longer. A dose delay was introduced for grade 3 nonhematologic toxicities, until toxicity was grade 2 or better; patients were then treated at one dose level lower, and therapy was discontinued if recovery time was 3 weeks or longer. Patients with drug-related grade 4 nonhematologic toxicities were treated at two dose levels lower at the first appearance and withdrawn at the second. A modified scale was used for hand–foot skin reaction (HFS), to facilitate interpretation (Table 1), and specific dose modifications were implemented (Table 2).
Response Assessment Investigator-assessed bidimensional tumor measurements were performed at baseline and every 8 weeks (two cycles), according to modified WHO criteria. Independent radiologic assessment was also performed for patients who had baseline and at least one postbaseline imaging measurement. Stable disease (SD) was required to last at least 16 weeks. Throughout the study, lesions measured at baseline were evaluated using the same technique and, preferably, by the same investigator. Overall tumor response was scored as a complete response (CR), partial response (PR), or minor response (MR; a reduction in tumor size of  25% but < 50% v baseline) if the response was confirmed at least 4 weeks later. Secondary objectives were duration of response (first administration of study drug until PD in patients with objective responses); TTP (first administration of study drug until PD); duration of SD (first day of receiving sorafenib until PD or response); overall survival (first day of receiving study medication to death). Patients who received at least one dose of sorafenib and had post-treatment data available were assessable for overall response rate.
Assessing Tumor Necrosis
PK
Biomarker Evaluation: Tumor-Cell Phosphorylated Extracellular Signal Regulated Kinase Levels
Biomarker Evaluation: Blood-Cell RNA Expression Patterns Quality-control procedures ensured that deviations in sample collection, freezing, storage, and shipping were minimized, and that resulting cRNA was of suitable quality for analysis on Affymetrix GeneChips. From a total of 240 whole-blood samples, only 52 (representing 32 patients) yielded cRNA of sufficient quality.
Statistical Analysis The first interim analysis considered the following: (a) 1 confirmed CR/PR; (b) 2 confirmed MRs; (c) 2 patients with at least 50% reduction in AFP; (d) 3 patients with either confirmed MRs or more than 50% reduction in elevated AFP or SD for 12 weeks. If none of these were met, the null hypothesis was accepted. If (a) was met, stage 2 could proceed. If (a) was not met but at least one of the other three conditions was met, stage 2 could proceed due to potential clinical benefit in the form of MRs, tumor marker reduction, and cytostatic and/or biomarker reduction. The first interim analysis suggested potential activity; therefore, patient enrollment was permitted to continue. The second interim analysis considered the following: (a) If five or fewer patients had confirmed CR or PR, the null hypothesis was accepted; (b) If at least 11 patients had confirmed CR or PR, the null hypothesis was rejected; (c) If six to 10 patients responded, accrual proceeded to stage 3. Stage 3 would accrue a cumulative total of 135 and consider the following: (a) If 14 or fewer patients had confirmed PR/CR, the null hypothesis was accepted. Patient recruitment was placed on hold, at the outset of the second interim analysis, to complete statistical analysis; however, investigators were permitted to enroll patients who were already in the screening phase. Due to rapid multicenter accrual, at the accrual hold, 147 patients had been screened and were eligible for enrollment.
Demographics The study enrolled 147 patients in Belgium, France, Italy, Israel, and the United States from August 2002 until June 2003, and all results are based on the treated population of 137 patients (Table 3). Ten patients did not meet the inclusion/exclusion criteria, and were registered as screening failures. Twelve patients were still receiving treatment as of May 16, 2004. Sixty-five percent had hepatitis B or C.
Dose and Duration of Therapy Median study duration was 3.4 months (range, 0 to 17.4 months), median number of treatment cycles was four (range, 1 to 19), and 72% of patients (92 of 128 patients) received six or fewer treatment cycles. Of the 132 patients who discontinued, 79 were because of disease progression, 27 because of adverse events, and 11 died.
Efficacy
Tumor Necrosis Despite tumors' appearing to have grown, many patients' scans displayed central TN. TN was assessed more rigorously in 11 patients (Fig 1). Tumors that increased in size (diameter and cross-product) demonstrated increases in TN. Baseline mean TN was 9.8% (range 0.4% to 33.5%), tumor diameter was 6.4 cm (range 2.5 to 14.2 cm), and cross-product was 28.9 cm2 (range 5.3 to 91.3 cm2). Follow-up mean TN was 27% (0.7% to 75%), tumor diameter was 7.2 cm (1.7 to 16.0 cm), and cross-product was 36.9 cm2 (2.1 to 162.5 cm2).
TTP and Survival On the basis of investigator assessment, median TTP was 4.2 months (Fig 2). On the basis of independent assessment, median TTP was 5.5 months (Fig 3), and median overall survival was 9.2 months (Fig 4).
Toxicity The most common drug-related adverse events (any grade) were dermatologic, constitutional, and GI (Table 5). Grade 3 toxicities included fatigue (9.5%), diarrhea (8.0%), and HFS (5.1%).
Sixty-day mortality was 10% of patients; 13 of 14 deaths within the first 60 days from starting therapy were related to PD. One death was secondary to an intracranial hemorrhage, but it is unclear whether it was drug related.
PK Data
Biomarker Evaluation: Tumor-Cell pERK Levels Thirty-three patients had tissue available for tumor-cell pERK staining and comparative analyses. In the majority of tumor samples, staining was generally most intense within the nucleus of tumor cells (Fig 6), and regional differences in the amount of staining were observed. There was a significant difference in TTP between patients with higher (2 to 4+, n = 18) tumor-cell pERK staining intensity, in archived specimens obtained before study treatment, versus those with lower intensity (0 to 1+, n = 15; P = .00034; Figs 6 and 7). Patients with tumors expressing higher pERK staining intensity had a longer TTP.
Levels of nonspecific background staining were very low, and were attributable to endogenous biotin, pigments, or residual peroxidase. There was also some evidence of pERK staining within most tumor samples, predominantly localized to the nuclei, in non-neoplastic cells including endothelial cells, fibroblasts, and lymphocytes.
Biomarker Evaluation: Blood-Cell RNA Expression Patterns
In this phase II trial, sorafenib was generally well tolerated and demonstrated antitumor activity in advanced HCC patients. HCC is a highly resistant solid tumor, and HCC cells have been shown to overexpress the multidrug resistance gene15 and gene product P-glycoprotein.16 HCC is associated with upregulation of dihydropyrimidine dehydrogenase, and thus is potentially resistant to chemotherapies such as fluorouracil.17,18 With the development of novel targeted therapies, there is an opportunity to evaluate these agents in HCC.19 Sorafenib demonstrated a median overall survival of 9.2 months, with 34% of patients achieving SD for at least 16 weeks and 8% achieving PRs or MRs. These data compare favorably with single-arm studies evaluating combination therapy (cisplatin, interferon, doxorubicin, and fluorouracil [PIAF] or doxorubicin plus cisplatin) in HCC patients.20,21 Median overall survival rates of 8.9 and 7.3 months and SD rates of 28% and 16%, respectively, for PIAF and doxorubicin/cisplatin regimens were reported.20,21 Despite differences in study designs, our results are not unlike median overall survival results from a recent randomized phase III trial by Yeo et al22 in HCC of doxorubicin versus PIAF; 6.8 and 8.7 months for doxorubicin and PIAF arms, respectively). A notable difference in the Yeo et al trial is the higher rate of HBV, which is consistent with an Asian population. There is also evidence that sorafenib may be combined successfully with other agents in HCC on the basis of a strong preclinical rationale and a favorable toxicity profile. Efficacy was demonstrated in a phase I combination study with sorafenib and doxorubicin in advanced HCC patients (one PR, one unconfirmed PR, and 61% SD).23 There is poor correlation between TN and conventional methods of response assessment, which poses questions of how best to quantify efficacy of sorafenib. Despite tumors' increasing in size, the observation of TN in this study is intriguing. Although the usefulness of TN in assessing efficacy of anticancer agents in HCC remains to be established, it is a potentially significant clinical end point that warrants further investigation. However, the relationship between tumor necrosis and clinical outcome remains to be determined. Relatively infrequent dose-limiting toxicities were observed. Notable grade 3/4 adverse events included fatigue, diarrhea, and HFS, which are commonly associated with sorafenib.11 The interpatient PK differences between CP A and B patients were not clinically relevant, because sorafenib was equally well tolerated by these two subgroups, and exposure values were similar to those reported in phase I studies that showed no relationship between PK variability and toxicity.11 Importantly, it is unlikely that dose adjustment would be necessary when administering sorafenib to patients with mild (CP A) or moderate (CP B) hepatic insufficiency. Several biomarkers have been shown to have potential predictive significance in HCC.24,25 Because the Raf/MEK/ERK pathway has a role in HCC, and is targeted by sorafenib, pERK may be a useful biomarker. Staining was most intense in nuclei of tumor cells in this study, consistent with translocalization of pERK to the nucleus after activation.26 Furthermore, HCC patients whose tumors expressed higher baseline pERK levels had a longer TTP following treatment with sorafenib. These data suggest that tumors containing higher levels of pERK are more sensitive, or responsive, to sorafenib. WBCs and peripheral blood mononuclear cells, the main sources of RNA isolated from whole blood, are considered a "surrogate tissue" relative to a primary tumor or metastasis.25 Therefore, gene-expression patterns of WBCs and peripheral blood mononuclear cells can be a molecular signature of a tumor that provides information on histologic stage or potential to respond to treatment. Although the RNA expression data from this study are encouraging, functional roles remain to be elucidated for the panel of genes that distinguished nonprogressors from progressors. Cell-based and genomic analyses will undoubtedly advance the discovery of new biomarkers for HCC, and help refine inclusion criteria and patient selection. Analysis with a larger number of patients in a placebo-controlled trial is required to validate whether components identified in this study may be used prospectively to predict response to sorafenib. Evaluation of sorafenib in combination with cytotoxic agents in HCC is ongoing.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We thank Douglas Bigwood, MD, for his contribution to the biomarker analyses.
published online ahead of print at www.jco.org on August 14, 2006. Presented at the 4th International Meeting on Hepatocellular Carcinoma: Eastern and Western Experiences, Hong Kong, December 14-16, 2004; European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Meeting, September 28-October 1, 2004, Geneva, Switzerland. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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INTRODUCTION
