Introduction

1. Efficacy and Safety of Single Agent Sunitinib in Treating Advanced Hepatocelluar Carcinoma Patients After Sorafenib Failure: A Prospective, Open-Label, Phase II Study TCC Yau,1,2,3 R Leung,1 J Chiu,1 H Wong,1 P Chan,4 T-T Cheung,2ACY Chan,2 R Pang,2,3 ST Fan,2,3 RTP Poon2,3 1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; 2Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong; 3Centre for Cancer Research, Faculty of Medicine, The University of Hong Kong, Hong Kong; 4Ruttonjee Hospital, Hong Kong.

2. Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer-related death Advanced HCC carries a poor prognosis, and systemic therapy with cytotoxic agents shows no survival benefit HCC is an aggressive, largely chemo-resistant cancer with poor prognosis Vascular endothelial growth factor (VEGF) is overexpressed in HCC and thought to contribute to tumor development Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

3. Introduction (cont’d) Sorafenib, an oral multikinase inhibitor, blocks tumor cell proliferation by targeting Raf kinase and tumor angiogenesis by inhibiting VEGF receptors Single agent sorafenib has been shown to prolong overall survival of patients with advanced HCC in two pivotal Phase III trials No proven systemic treatment option after progression with sorafenib Sunitinib, an oral multitargeting tyrosine kinase inhibitor with a target inhibition profile that partially overlaps sorafenib, inhibits pathways that have been implicated in angiogenesis and inflammation in advanced HCC Phase II studies employing different doses of sunitinib suggested initial activity of single-agent sunitinib in treating advanced HCC A recent randomized Phase III sunitinib study was halted early because of concerns about efficacy and treatment-related toxicities Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

4. Aims and Methods Open-label and single-arm Phase II study to assess the efficacy and tolerability of sunitinib for the treatment of patients with sorafenib-refractory advanced HCC Patients with advanced HCC with documented disease progression after sorafenib treatment received sunitinib 37.5 mg continuously at Queen Mary Hospital, Hong Kong Screening upper endoscopy was used to exclude significant varices prior to enrollment Tumor responses were assessed after every 8 weeks (RECIST) Primary endpoint: time-to-progression (TTP) Secondary endpoints: response rate (RR), overall survival (OS), and safety RECIST=Response Evaluation Criteria In Solid Tumors. Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

5. Patient Demographics 38 Asian patients were enrolled between October 2008 and August 2010 • 32 patients (80%) had extrahepatic metastasis BCLC=Barcelona Clinic Liver Cancer staging; ECOG PS=Eastern Cooperative Oncology Group PerformanceStatus; HBV=hepatitis B virus; HCV=hepatitis C virus. Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

6. Efficacy • Median TTP was 2.9 months (range, 0.5-15) • Median OS was 5.2 months (range, 1-22.5) Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

7. Safety Most treatment-related toxicities were Grade 1 or 2 Malaise (60%), neutropenia (45%), and diarrhea (36%) were the most commonly encountered adverse events (AEs) Malaise (15%) and impaired liver function (20%) were the most commonly encountered Grade 3 or 4 AEs No variceal bleeding was observed No treatment-related death was reported Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

8. Conclusions • Current data suggest that sunitinib has substantial antitumor activity with a manageable toxicity profile in treating a sorafenib-refractory advanced HCC population • Results imply that sunitinib inhibits signaling pathways involved in sorafenib resistance • Findings support the hypothesis of sequential use of antiangiogenic tyrosine kinase inhibitors in treating patients with advanced HCC • Future randomized trials may vigorously examine the role of sunitinib in treating a sorafenib-refractory advanced HCC population Adapted from Yau TCC et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.