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