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Disclosures Participated in the following Advisory Boards: Gilead

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1 Disclosures Participated in the following Advisory Boards: Gilead
Hoffman La Roche Janssen Merck Vertex Kathy Poldre CAHN 2013

2 Liver Cancer is the Sixth Most Common Cancer Worldwide1
Lung 1.5 million Breast 1.3 million Colon/Rectal 1.1 million Stomach 1 million Prostate 782,000 Liver 711,000 Cervix Uteri 559,000 Esophagus 529,000 Leukemia 330,000 Bladder 314,000 Ovary 230,000 Liver cancer is the sixth most common cancer worldwide, accounting for 711,128 (5.8%) of new cases per year in HCC is the most common primary tumor of the liver in adults.2 Corpus Uteri 226,000 Oral Cavity 200,000 Non-Hodgkin's Lymphoma 196,000 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000 HCC is the most common primary liver malignancy in adults2 1. Garcia M, et al. American Cancer Society, Accessed March 20, 2008. 2. Perz JF, et al. J Hepatol. 2006;45: Garcia M, Jemal A, Ward EM, et al. Global Cancer Facts & Figures Atlanta, GA: American Cancer Society; Accessed March 20, 2008. Perz JF, Armstrong GL, Farrington LA, Hutin YJF, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:

3 Number of estimated deaths
Liver Cancer is the Third Most Common Cause of Cancer-Related Mortality Globally 1,600,000 1.3 million 1,400,000 1,200,000 1,000,000 800,000 Number of estimated deaths 800,000 679,000 602,000 600,000 Liver cancer is the third most common cause of cancer-related mortality globally, with the total number of deaths estimated at 679,871 per year. ADDITIONAL INFORMATION Liver cancer is the third most common cause of cancer-related mortality in men and the sixth in women, around the world. The estimated 5-year survival rates are less than 11% in underdeveloped and developed countries. 400,000 200,000 Lung and bronchus Stomach Liver Colon and rectum Liver cancer is the third most common cause of cancer-related death Garcia M, et al. American Cancer Society, Accessed August, 2008. Garcia M, Jemal A, Ward EM, et al. Global Cancer Facts & Figures Atlanta, GA: American Cancer Society; Accessed August 2008.

4 HCC Risk Factors Are Well Defined and Show Geographical Variation
Europe and North America Asia and Africa (excluding Japan) Japan Hepatitis C virus (50-70%) Hepatitis B virus (70%) Hepatitis C virus (70%) HBV (10-20%) HBV (10-20%) HCV (20%) Alcohol (20%) Other (10%) Alcohol (10%) Alcohol (10%) Other (<10%) Other (<10%) Adapted from Llovet JM, et al. Lancet. 2003;362:

5 AASLD Diagnostic Criteria for HCC
Mass on surveillance ultrasound (US) in a cirrhotic liver <1 cm 1-2 cm >2 cm Repeat US every 3-4 mo Two dynamic imaging studies One dynamic imaging technique Coincidental typical vascular pattern Typical vascular pattern with 1 technique Atypical vascular pattern with both techniques Atypical vascular pattern Typical vascular pattern on dynamic imaging or AFP >200 ng/mL Stable >18-24 mo Enlarging Biopsy This is the AASLD-suggested algorithm for evaluation of a nodule found by ultrasound during screening or surveillance. Nodules that are smaller than 1 cm should be followed with ultrasound at 3- to 4-month intervals. If there is no growth over a period of up to 2 years, then the patient can return to the standard surveillance every 6-12 months. Nodules between 1 and 2 cm found by ultrasound in a cirrhotic liver should be examined by 2 dynamic imaging studies, CT scan, contrast ultrasound, or magnetic resonance imaging (MRI) with contrast. If the appearance is typical of HCC, (ie, hypervascular in the arterial phase with washout in the portal/venous phase) in 2 of the imaging techniques, then the nodule should be treated as HCC. If the findings are not characteristic of HCC or if the vascular profile is not coincidental by both techniques, then the nodule should be biopsied. If the nodule is larger then 2 cm and it has the features typical of HCC by 1 dynamic imaging technique and/or AFP levels are higher than 200 ng/mL, biopsy is not necessary for the diagnosis of HCC. However, if the vascular profile is atypical or if the nodule is detected in a noncirrhotic liver, the lesion should be biopsied. Diagnostic of HCC Nondiagnostic of HCC Other diagnosis Return to surveillance every 6-12 mo Repeat biopsy or imaging follow-up Change in size/profile Proceed according to lesion size + Repeat imaging and/or biopsy - Adapted from Bruix J and Sherman M. Hepatology. 2005;42(5): Treat as HCC Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology ;42(5):

6 HCC treatment algorithm (BCLC)
PST 0, Child-Pugh A PST 0-2, Child-Pugh A-B PST > 2, Child-Pugh C Very early stage Early stage Intermediate stage Advanced stage Terminal stage Single < 2 cm Single or 3 nodules ≤ 3 cm, PST 0 Multinodular, PST 0 Portal invasion, N1, M1, PST 1-2 Single 3 nodules ≤ 3 cm HCC, hepatocellular carcinoma; LT, liver transplantation; PEI/RF, percutaneous ethanol injection/radiofrequency ablation; PST, performance status test; RCT, randomized clinical trial; TACE, transcatheter arterial chemoembolization. Staging and the recommended treatment of patients with HCC according to BCLC classification are as follows: Very early and early stage cases receive potentially curative treatments: resection, liver transplantation, and percutaneous therapy Intermediate stage HCC is mainly treated by transcatheter arterial chemoembolization (TACE)  based on results from randomized clinical trials Advanced stage HCC’s standard of care is now sorafenib, based on data from a recent randomized clinical trial[1]   Terminal stage HCC, at present, is treated with  best supportive care Reference Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359: Portal pressure/bilirubin Portal invasion, N1, M1 Increased Associated diseases Normal No Yes No Yes Resection Liver transplant PEI/RF TACE Sorafenib Curative treatments Symptomatic (unless LT) Llovet JM, et al. J Natl Cancer Inst. 2008;100: Bruix J, et al. Hepatology. 2005;42: 6

7 BCLC Staging System and Treatment Algorithm
HCC Very Early Stage Early Stage Intermediate Stage Advanced Stage End Stage Surgical Treatment Local Ablation TACE Sorafenib Symptomatic treatment Patients diagnosed with very early and early stage HCC could be treated with potentially curative treatments, such as resection, liver transplantation, or ablation. If patients were diagnosed with intermediate stage HCC, transarterial chemoembolization (TACE) is the suggested treatment. Palliative care is applied to patients with end-stage HCC. Prior to sorafenib, patients diagnosed with advanced stage HCC had few treatment options. ~30% patients ~20% patients ~30% patients ~20% patients 5-year survival: 40%-70% (treated) ~20% (untreated) Median survival: ~19-20 months (treated) ~16 months (untreated) Median survival: ~10-11 months (treated) ~6-7 months (untreated) Median survival: <3 months ADDITIONAL INFORMATION Previous studies have shown that patients treated with resection or liver transplantation had a 5-year survival rate of 40% to 70%. Patients treated with ablation had a 5-year survival rate of 40% to 50%. If a patient with intermediate or advanced HCC remains untreated, the median survival is 11 to 20 months. When diagnosed at an advanced stage, survival is <3 months. Most patients with HCC are not diagnosed until they have intermediate or advanced HCC, resulting in poor patient prognosis, since few treatment options are possible at these stages of HCC. TACE = transarterial chemoembolization Adapted from Llovet JM, et al. J Natl Cancer Inst. 2008;100: Llovet JM, DiBisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100(10):

8 Treatment Options Limited by liver function and characteristics of the malignant lesion i.e. Vascular invasion Solitary vs Multifocal disease Location of lesion(s) – close to vital structures Size of lesion(s) Childs Pugh Score Very early, early, intermediate  transplant

9 Nexavar ® (Sorafenib) Treatment of Advanced Hepatocellular Carcinoma
Kathy Poldre CAHN 2013

10 Indications Nexavar® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

11 Sorafenib Targets Tumor Cell Proliferation and Angiogenesis
Endothelial Cell or Pericyte HGF Paracrine stimulation PDGF-b VEGF Autocrine loop PDGFR-b VEGFR-2 Apoptosis RAS RAS RAF Mcl-1 RAF Mitochondria Sorafenib MEK Sorafenib Mitochondria MEK Angiogenesis: Sorafenib can target both tumor cell proliferation and angiogenesis.1,2 Inhibition of the Raf/MEK/ERK pathway can increase tumor cell apoptosis, and reduce tumor cell proliferation, survival, autocrine hepatocyte growth factor (HGF) signaling, as well as decrease the secretion of proangiogenic factors in response to intratumoral hypoxia.3,4 In addition to reducing paracrine signaling from tumor cells to the vascular endothelium via growth factor secretion, sorafenib can directly target angiogenesis by inhibiting VEGF receptors -1, -2, and -3, as well as the PDGF receptor, increasing endothelial cell/pericyte apoptosis, and downregulating the expression of genes associated with blood vessel formation.3,4 Differentiation HIF ERK HGF Apoptosis ERK Proliferation PDGF Migration VEGF Nucleus Tubule formation Proliferation Nucleus Survival HGF = hepatocyte growth factor. Avila MA, et al. Oncogene. 2006;25: ; Liu L, et al. Cancer Res. 2006;66: ; Semela D, et al. J Hepatol. 2004;41: ; Wilhelm SM, et al. Cancer Res. 2004;64: Wilhelm SM, Carter C, Tang L, et al. BAY exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64: Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66: Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006;25: Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41:

12 Dosing Continuous daily dosing 400 mg (2 x 200 mg tablets) twice daily
No dose adjustments for age, gender, or body weight Can be administered without food or low-moderate fat diet

13 Sorafenib in Advanced HCC: The SHARP Trial
Entry criteria Advanced HCC Not eligible for or failed surgical or locoregional therapies Child-Pugh class A disease At least 1 untreated target lesion Exclusions Previous chemotherapy Previous molecularly targeted therapy HCC, hepatocellular carcinoma; SHARP, Sorafenib HCC Assessment Randomized Protocol. The phase III SHARP trial was a landmark study that resulted in the approval of sorafenib and established it as the standard of care in the setting of advanced HCC because of significant improvements in median survival and time to progression compared with placebo. The SHARP study enrolled patients with advanced stage HCC who were not eligible for or had failed surgical or locoregional therapies. Child‑Pugh class A disease was required as was the presence of at least 1 untreated target lesion that could be measured in terms of response. Exclusion criteria included previous chemotherapy or previous molecularly targeted therapy. Llovet JM, et al. N Engl J Med. 2008;359: 13

14 SHARP Trial: Baseline Characteristics
Sorafenib (n = 299) Placebo (n = 303) Median age, yrs 64.9 66.3 Male, % 87 BCLC stage, % B (intermediate) 18 17 C (advanced) 82 83 Vascular invasion, % 70 BCLC, Barcelona Clinic Liver Cancer; SHARP, Sorafenib HCC Assessment Randomized Protocol. The baseline characteristics of patients enrolled in the SHARP study included a mean age of approximately 65 years; the majority were male (this is a male‑predominant disease); an intermediate or advanced BCLC stage (more than 80% were BCLC stage C); and macroscopic vascular invasion visible on imaging in approximately 70% of patients. Llovet JM, et al. N Engl J Med. 2008;359: 14

15 The SHARP Trial: Drug-Related AEs
Sorafenib (N = 297) Placebo (N = 302) P Value Any Grade Grade 3 Grade 4 Grade 3 or 4 IGI Events Anorexia 14 < 1 3 1 < .001 1.0 Diarrhea 39 8 11 2 Voice changes 6 NA Hypertension 5 .05 .28 Liver dysfunction .50 Abdominal pain not otherwise specified .007 .17 Bleeding 7 4 .07 1.00

16 The SHARP Trial: Drug-Related AEs
Sorafenib (N = 297) Placebo (N = 302) P Value Any Grade Grade 3 Grade 4 Grade 3 or 4 Overall incidence 80 52 Constitutional symptoms Weight Loss 9 2 1 <0.001 1.0 Dermatologic events Alopecia 14 NA Dry skin 8 4 0.4 Hand-foot skin reaction 21 3 <1 Other 5 0.12

17 Hand-Foot Syndrome A fairly severe example of hand‑foot syndrome is shown on this slide. More often, hand-foot syndrome manifests as very dry skin with flaking that may progress and make walking uncomfortable. Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161. 17

18 Grading of Hand-Foot Syndrome
Grade Symptom 1 Minimal skin changes or dermatitis (eg, erythema) without pain 2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function 3 Skin changes with pain, interfering with function The common toxicity criteria for adverse events system is used to grade hand‑foot syndrome. Common Terminology Criteria for Adverse Events, Version 3.0. Available at: Accessed October 13, 2008. 18

19 Dose modification recommendations
Temporary interruption and /or dose reduction of management of AEs Reduced to 400 mg once daily If necessary, single 400 mg dose every other day

20 Strategies for Managing AEs
Hand-foot syndrome - Lanolin containing creams and lotions Avoid tight footwear, protect feet May require dose reduction Diarrhea Antidiarrheal agents –Immodium Carbohydrates : rice, potatoes - bulk forming agent - Separate solids from fluids Hypertension Start or adjust antihypertensives AEs, adverse events. This slide lists strategies for managing sorafenib-associated adverse events. 20

21 SHARP: Exploratory Subgroup Survival Analysis
Favors Nexavar Favors Placebo ECOG PS 0 ECOG PS 1 & 2 No extrahepatic spread Extrahepatic spread No macroscopic vascular invasion Macroscopic vascular invasion No macroscopic VI/extrahepatic spread Macroscopic VI and/or extrahepatic spread 0.5 1.0 1.5 0.0 HR (95% CI) for Survival Llovet JM, et al. J Clin Oncol. 2007;25(suppl 18):LBA1. Updated from oral presentation.

22 Case Study Mr. H: 79 yr old, 6 children HBV
2009- Hong Kong  fatigue, hematuria, wt loss Investigations: benign prostatic hypertrophy - mass in the liver CT Oct 2009 : 9 cm x 12 cm mass Seg 6 & 7 - another lesion 8.8 cm Seg 7 - suspicious lymph node

23 Mr. H (cont’d) Would think about treatment – TACE
March 17, 2010 – started on Sorafenib, 200 mg bid to assess tolerability March 25, 2010 – mod-severe hand/foot syn. drug stopped x 1wk, restarted 200 mg OD April 29, 2010 – dose 400mg OD

24 Mr. H (cont’d) May 26, ’10 – loss of appetite -hand/foot continues (blisters) June 21’ 10 – hand/foot continues -desquamating rash on heals - CT scan – stable ; will put up with the discomfort for the benefit Aug 19’ 10 – off for a few weeks waiting EAP reapproval. Restarts on full dose

25 Mr. H. (cont’d) Sept 2010 – present - 83 years old
- tolerating drug well - good response to Sorafenib “stable disease with no evidence of progression” - good liver function, Childs Pugh A, PS 1

26 Mr. H (cont’d) CT Oct 13, 2009 Seg 6/7 lesion – 12.8 cm x 8.9 cm
Seg 7 – 8.8 cm CT Jan 2, 2013 Seg 6/7 – 9.1 cm x 6.7 cm Seg 7 – 4.9 cm

27 CT Scans October 13, 2009 January 2, 2013

28 Sorafenib is the Systemic Treatment Standard in HCC
Sorafenib is the first and only drug ever proven to extend overall survival in patients with HCC Two randomized phase III studies demonstrate that sorafenib prolongs overall survival and time to progression in both Western and Asian patient populations Sorafenib prolongs overall survival irrespective of patient characteristics or extent of disease Sorafenib is safe and manageable in patients with HCC Drug-related adverse events are generally mild-to-moderate, predictable and manageable In summary, the OS, TTP, and PFS hazard ratios were similar in the SHARP and the Asia-Pacific studies, despite more advanced disease in the Asia-Pacific liver cancer study patients. Therefore, it can be concluded that sorafenib is safe and efficacious in patients with HCC across geographic regions.

29 Thank you

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