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

Disclosures

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

Liver Cancer is the Sixth Most Common Cancer Worldwide1

• HCC is the most common primary liver malignancy in adults2

1. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008. 2. Perz JF, et al. J Hepatol. 2006;45:529-538.

196,000

226,000

230,000

200,000

314,000

330,000

529,000

559,000

711,000

782,000

1 million

1.1 million

1.3 million

1.5 million

0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000

Non-Hodgkin's Lymphoma

Corpus Uteri

Ovary

Oral Cavity

Bladder

Leukemia

Esophagus

Cervix Uteri

Liver

Prostate

Stomach

Colon/Rectal

Breast

Lung

Liver Cancer is the Third Most Common Cause of Cancer-Related Mortality Globally

• Liver cancer is the third most common cause of cancer-related death

1.3 million

800,000

679,000602,000

Lung and bronchus

Stomach Liver Colon and rectum

Nu

mb

er o

f es

tim

ated

dea

ths

Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed August, 2008.

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

HCC Risk Factors Are Well Defined and Show Geographical Variation

Hepatitis C virus(50-70%)

HBV(10-20%)

Alcohol(20%)

Other(10%)

Europe and North America

Asia and Africa (excluding Japan) Japan

HCV(20%)

Hepatitis B virus (70%)

Alcohol(10%)

Hepatitis C virus(70%)

HBV(10-20%)

Alcohol(10%)

Other(<10%)

Adapted from Llovet JM, et al. Lancet. 2003;362:1907-1917.

Other(<10%)

AASLD Diagnostic Criteria for HCCMass on surveillance ultrasound (US) in a cirrhotic liver

Stable >18-24 mo Enlarging

Return to surveillance

every 6-12 mo

Proceed according to lesion size

Nondiagnostic of HCC

Change insize/profile

Repeat biopsy or imaging follow-up

Repeat imaging and/or biopsy + -

Other diagnosis

Diagnostic of HCC

<1 cm 1-2 cm >2 cm

One dynamic imaging technique

Repeat USevery 3-4 mo

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

Treat as HCC

Biopsy

Two dynamic imaging studies

Adapted from Bruix J and Sherman M. Hepatology. 2005;42(5):1208-1236.

HCC treatment algorithm (BCLC)

Liver transplant PEI/RF

Curative treatments

TACE

HCC

Single

Increased Associateddiseases

Normal No Yes No Yes

Terminalstage

PST 0-2, Child-Pugh A-B

Multinodular, PST 0

Portal invasion, N1, M1

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Intermediate stage

PST > 2, Child-Pugh C

Very early stageSingle < 2 cm

Early stageSingle or 3 nodules

≤ 3 cm, PST 0

Advanced stagePortal invasion,

N1, M1, PST 1-2

PST 0, Child-Pugh A

Resection

Symptomatic (unless LT)

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.

BCLC Staging System and Treatment Algorithm

End StageAdvanced StageIntermediate StageVery Early Stage

Early Stage

Surgical TreatmentLocal Ablation SorafenibTACE

HCC

~30% patients ~20% patients ~20% patients

TACE = transarterial chemoembolizationAdapted from Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

~30% patients

Symptomatic treatment

5-year survival: 40%-70% (treated)~20% (untreated)

Median survival: ~19-20 months (treated)~16 months (untreated)

Median survival:<3 months

Median survival: ~10-11 months (treated)~6-7 months (untreated)

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

Nexavar ® (Sorafenib)

Treatment of AdvancedHepatocellular Carcinoma

Kathy PoldreCAHN 2013

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).

Sorafenib Targets Tumor Cell Proliferation and Angiogenesis

RAS

Endothelial Cell or Pericyte

ProliferationMigration

Angiogenesis:

Tubule formation

PDGF- VEGF

VEGFR-2PDGFR-

Paracrine stimulation

Differentiation

Mitochondria

Apoptosis

Tumor Cell

PDGFVEGFProliferationSurvival

Mitochondria

HIF

Nucleus

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

RAFMcl-1

Avila MA, et al. Oncogene. 2006;25:3866-3884; Liu L, et al. Cancer Res. 2006;66:11851-11858;Semela D, et al. J Hepatol. 2004;41:864-880; Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109.

HGF

HGF

Autocrineloop

SorafenibSorafenib

HGF = hepatocyte growth factor.

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

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

Llovet JM, et al. N Engl J Med. 2008;359:378-390.

SHARP Trial: Baseline Characteristics

Characteristic Sorafenib(n = 299)

Placebo(n = 303)

Median age, yrs 64.9 66.3

Male, % 87 87

BCLC stage, %

B (intermediate) 18 17 C (advanced) 82 83

Vascular invasion, % 70 70

Llovet JM, et al. N Engl J Med. 2008;359:378-390.

The SHARP Trial: Drug-Related AEs

AE’s (%) Sorafenib (N = 297) Placebo (N = 302) P Value

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3 or 4

IGI Events

Anorexia 14 < 1 0 3 1 0 < .001 1.0

Diarrhea 39 8 0 11 2 0 < .001 < .001

Voice changes 6 0 0 1 0 0 < .001 NA

Hypertension 5 2 0 2 1 0 .05 .28

Liver dysfunction < 1 < 1 0 0 0 0 .50 .50

Abdominal pain not otherwise specified

8 2 0 3 1 0 .007 .17

Bleeding 7 1 0 4 1 < 1 .07 1.00

The SHARP Trial: Drug-Related AEs

AE’s (%) Sorafenib (N = 297) Placebo (N = 302) P Value

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3 or 4

Overall incidence 80 52

Constitutional symptoms

Weight Loss 9 2 0 1 0 0 <0.001 1.0

Dermatologic events

Alopecia 14 0 0 1 0 0 <0.001 NA

Dry skin 8 0 0 4 0 0 0.4 NA

Hand-foot skin reaction

21 8 0 3 <1 0 <0.001<0.00

1

Other 5 1 0 1 0 0 <0.001 0.12

Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.

Hand-Foot Syndrome

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

Common Terminology Criteria for Adverse Events, Version 3.0. Available at: http://ctep.cancer.gov. Accessed October 13, 2008.

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

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

SHARP: Exploratory SubgroupSurvival Analysis

Favors Nexavar Favors Placebo

HR (95% CI) for Survival0.5 1.0 1.50.0

ECOG PS 1 & 2

No macroscopic vascular invasionMacroscopic vascular invasion

No macroscopic VI/extrahepatic spreadMacroscopic VI and/or extrahepatic spread

Extrahepatic spreadNo extrahepatic spread

ECOG PS 0

Llovet JM, et al. J Clin Oncol. 2007;25(suppl 18):LBA1. Updated from oral presentation.

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

Mr. H (cont’d)

Would think about treatment – TACEMarch 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 ODApril 29, 2010 – dose 400mg OD

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 benefitAug 19’ 10 – off for a few weeks waiting EAP

reapproval. Restarts on full dose

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

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

CT Scans

October 13, 2009 January 2, 2013

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

Thank you