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DISCLAIMER
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients conditions and possible contraindications on dangers in use, review of any applicable manufacturers product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USE

This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of Interest

Robert G. Gish, MD Reported a financial interest/relationship or affiliation in the form of: Consulting Fee, Bayer Pharmaceuticals Corporation, Onyx Pharmaceuticals, Inc.; Speakers Bureau, Bayer Pharmaceuticals Corporation, Onyx Pharmaceuticals, Inc.

Activity Agenda
o Introduction 5 mins o Overview of Epidemiology and Diagnosis of HCC 10 mins o Current and Emerging Management of HCC: Surgical Management, Loco-Regional Therapy, and Targeted Therapy Development 30 mins o Practical Application Cases 15 mins

Learning Objectives
Upon completion of this activity, participants should be better able to:
o Identify risk factors associated with HCC, including underlying liver disease, and to thoroughly assess patients upon presentation o Implement appropriate treatment plans for patients with HCC according to patient and tumor characteristics and evidence-based clinical guidelines o Evaluate recent trial data targeting novel agents being evaluated for the treatment of patients with advanced HCC and the potential impact these therapies may have on the current standard of care o Devise strategies to integrate novel targeted agents into treatment plans for patients with advanced HCC o Implement a more successful multidisciplinary approach for treating HCC based on expert and evidence-based recommendations

Demographic Question 1
If you are a physician, what is your primary specialty?
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Medical oncology Surgical oncology Radiation oncology Radiation (non-oncology) Internal medicine/primary care Gastroenterology Hepatology Pathology Medical oncology fellow Other physician

Demographic Question 2
If you are not a physician, what is your primary specialty?
1. 2. 3. 4. 5. 6. 7. 8. 9. Pharmacy Nurse Nurse practitioner Physician assistant Research Data monitoring Industry Academic Other

Demographic Question 3
In a typical month, how many patients with hepatocellular carcinoma do you treat?
1. 2. 3. 4. 5. 6. 15 610 1115 1620 > 20 I do not treat patients with hepatocellular carcinoma

Practice Patterns and Trends Survey Question 1

What treatment do you utilize most often for a patient with unresectable HCC who is not a transplant candidate?
1. 2. 3. 4. 5. 6. 7. 8. Sorafenib Clinical trial Ablation TAE TACE Radioembolization with Yttrium-90 microspheres Stereotactic body radiation therapy Other

Practice Patterns and Trends Survey Question 2

Please rate your level of knowledge regarding sorafenib for the treatment of HCC.
1. 2. 3. 4. No knowledge Limited knowledge Somewhat knowledgeable Very knowledgeable

Practice Patterns and Trends Survey Question 3

Please rate your level of knowledge regarding novel targeted agents for the treatment of HCC.
1. 2. 3. 4. No knowledge Limited knowledge Somewhat knowledgeable Very knowledgeable

Practice Patterns and Trends Survey Question 4

Please rate your level of knowledge regarding the mechanism of action of ramucirumab.
1. 2. 3. 4. No knowledge Limited knowledge Somewhat knowledgeable Very knowledgeable

Overview of Epidemiology and Diagnosis of HCC

Pre-Assessment Question 1
Which of the following regarding LI-RADS is true?
1. A system of standardized terminology and criteria to interpret and report imaging examinations of the liver 2. Currently applies to patients with cirrhosis or at risk for HCC 3. Categorizes observations from LR1 to LR5, reflecting probability of benignity or HCC in at-risk patients 4. 1 and 2 only 5. 2 and 3 only 6. All of the above

Hepatocellular Carcinoma (HCC)

o 5th most common cancer in men; 7th in women worldwide o 3rd leading cause of death from cancer worldwide o Incidence and death rate rising whereas many other cancer mortality rates are decreasing o Primarily due to Hepatitis B, C and non-alcoholic steatohepatitis (NASH) o Global HCC: Every 30 seconds, one person in the world dies from liver cancer. These deaths are preventable! o > 80% of cases occur in people from sub-Saharan Africa, S-E Asia and eastern Mediterranean o This geography makes up 45% of worlds population
Monsour et al, 2013.

Victims of HCC

Ray Charles Johannes Brahms dith Piaf

Epidemiology: USA 2014 Estimations

Incidence: 33,190
24,600 8,590

Deaths: 23,000

15,870

7,130

Siegel et al, 2014.

US Burden of Diseases, 1990-2010

YLL YLL Rank 1990 2010 7 14 39 23 8 30 Deaths (in thousands) 1990 2010 28.6 12.1 ( 57.7%) 35.5 49.5 ( 43.3%) 9.3 19.5 ( 118.4%) DALY 1990 2010 11 21 33 16 -

HIV/AIDS Cirrhosis Liver Cancer

64.5% 38% 125.5%

YLL = Years of Life Lost; DALY = Disability Adjusted Life Years. US Burden of Disease Collaborators, 2013.

Liver Cancer Mortality, US, 2000-2010

National Cancer Institute.

Mortality From Cancer In Obese Men

Calle et al, 2003.

Pathogenesis of Hepatocellular Carcinoma

CH 15-40 years Cirrhosis 3-5% per year
pRb1 Pathway Early genetic alterations?? Epigenetic alterations HBV e HCV Diabetes NASH Alcohol Wnt pathway
-catenin (axin>APC) (pRb1 LOH, p27, p16 cyclin D1, gankirin)

HCC

TGF-1 Pathway p53 family

P53 (mutations if aflatoxin exposure) p73 altered expression

Aflatoxins

Inflammation

Dysplastic Lesions

Clonal Selection

Adapted from Levrero, 2006.

Relevant Pathways in HCC Biology

Avila et al, 2006.

Molecular Signatures: Etiology, Survival, Metastasis & Stem Cells

1.0
P=4.31 x 10-5

0.8 0.6
Probability
Cluster B
Cluster A Pathways Proliferation Anti-apoptotic Ubiquitination Hypoxia-induced DNA instability

0.4 0.2
Cluster A

0.0 0 50 100 150 200

Survival (months)
Lee et al, 2004.

PI3K/AKT/mTOR Pathway
Growth factor
Cell membrane Growth factor receptor

P
PI3K PTEN mTOR Complex 2
mTOR

PDK1
AKT mTOR
Bad

mLST8 SIN1

rictor

Cell survival

mTOR Complex 1 raptor

Actin cytoskeleton

mLST8

P70 S6K 4E-BPI

Cell cycle progression G1-S

Adapted from Llovet et al, 2008.

Translation of cell cycle regulatory protein

Targeted Therapy for HCC

VEGF Inhibitor or Anti-VEGF Antibody Advanced/ Metastatic HCC

Receptor Tyrosine Kinase Inhibitor

Intermediate HCC

Angiogenesis Metastasis Pathways

Early HCC

Dysregulated Growth Pathways

Courtesy of Robert G. Gish, MD.

Burrel et al: MRI angiography (MRA) superior to helical CT for detection of HCC
Detection of main HCC and additional nodules pre-transplantation vs in explanted livers: Sensitivity of MRA and helical CT CT (%) Variables Pathology MRA (%)*
Per-patient basis (n=29)
Sensitivity (detection) Sensitivity (characterization) Specificity Accuracy Per-nodule basis (n=76), sensitivity analysis* All HCC nodules >20 mm 1020 mm <10 mm 76 25 28 23 76 (58/76) 100 (25/25) 89 (25/28) 34 (8/23) 61 (43/70) 100 (24/24) 65 (17/26) 10 (2/10) 100 90 95 98 100 96 NA NA

*MRA was performed in 50 cirrhotic patients; 29 patients presented 76 nodules Helical CT: Triphasic helical CT was performed in 26 of 29 HCC patients, presenting a total of 70 nodules

CT = computed tomography; MRA = magnetic resonance angiography. Burrel et al, 2003.

Liver-Specific MRI Contrast Agents

o Gadoxetate Disodium
T1 agent: extracellular + hepatocyte Excretion: 50% renal, 50% liver Hepatocyte phase: 20 minutes (in addition to dynamic enhancement) Lesions lacking hepatocytes have no uptake on hepatocyte phase (cyst, metastases, most HCCs) Can visualize the bile ducts

EOVIST (gadoxetate disodium) Injection, bayerimaging.com.

Surveillance for HCC Reduces Mortality: A Randomized Controlled Trial

o Survival rate higher in screening vs control group (P < .01) 0.8 Survival Probability, % 0.6 0.4 0.2 0.0 Control Screening

0
Zhang et al, 2004.

Time, Years

Percutaneous Ablative Therapies for Hepatocellular Carcinoma

Percutaneous ethanol injection Acetic acid injection Hot saline injection Radiofrequency Microwaves Cryoablation Laser

Chemical ablation

Thermal ablation

Irreversible electroporation Light-activated drug therapy

New non chemical/non thermal

Adapted from Lau et al, 2003.

Survival Rates of Asian American Patients With HCC by Treatments

Patient Survival OLT all Resection all 100 80 Survival, % 60 40 20 0 RFA only

TACE only
TACE RFA other Supportive care

30

60 90 Months of Follow Up

120

150

OLT = orthotopic liver transplantation; RFA = radiofrequency ablation; TACE = transcatheter arterial chemoembolization. Tong et al, 2010.

HCC Is Inhibited in HCV Patients With Sustained Viral Response and Sustained Biochemical Response Following Treatment With IFN + RBV
3-year cumulative incidence
5-year cumulative incidence
Cumulative Incidence of HCC (%)

All Patients (N=420)

SVR (n=181)

Non-SVR (n=239)

Non-SVR, SBR (n=131)

Non-SVR, Non-SBR (n=108)

SVR = sustained viral response; SBR = sustained biochemical response; IFN = interferon; RBV = ribavirin; HCV = hepatitis C virus. Nakajima et al, 2009.

Not All HCC Make All Biomarkers Patient number of AFP-L3%, DCP and AFP in those with Known HCC (n=685)
AFP > 20
DCP > 40
93

96

110
15

153 45 14

AFP-L3% > 10
AFP = alpha-fetoprotein; DCP = des-gamma-carboxy prothrombin; AFP-L3 = lens culinaris agglutinin A-reactive fraction of AFP. Toyoda et al, 2006.

159 (23%) all negative

Utility When Biomarkers are Used in Combination in patients with no known HCC: False Positives
False Positive AFP: 25% AFP-L3%: 7% DCP: 9% AFP-L3% True Negative

15
(3.7%)

258 (64%)

3
(0.7%)

9 2
(0.5%)

(2.2%)

26
(6.5%)

7
(1.7%)

81(20.2%)
AFP

DCP N = 401
Sterling et al, 2009.

How Do We Use AFP ?

o AFP is a useful biomarker of a patient's increased future RISK for HCC o AFP is not a screening or surveillance tool for HCC

Wakodiagnostics.com

AFP L3% Rises before AFP in Typical Course of HCC Occurrence Case
Before HCC diagnosis Tumor size: 2 cm

HCC diagnosis Tumor size: 3-5 cm

AFP: ng/mL

21 months

Months
AFP conc.
Sterling et al, 2012.

AFP-L3 conc.

AFP-L3%

AFP-L3%

Proposed Liver Ultrasound Algorithm

Poor/Fair quality US Or abnormal biomarkers
#gadoxetate

disodium MRI (Or dynamic CT)

Liver Dedicated Surveillance Ultrasound (US) + HCC biomarkers in at-risk patients* Good/Excellent quality US and normal HCC biomarkers
blood

Negative MRI

US surveillance q6 months with biomarkers

Abnormal US or increasing biomarkers

tests AFP-L3%/DCP (HCC serum biomarkers); *AASLD Guidelines 2009; # see LI-RADS. AASLD = American Association for the Study of Liver Diseases; AFP = alpha-fetoprotein; CT = computed tomography; DCP = des-gamma-carboxy prothrombin; HCC = hepatocellular carcinoma; LI-RADS = Liver Imaging Reporting and Data System; MRI = magnetic resonance imaging; US = ultrasound. Gish, 2014.

HCC Lesions Eligible for Automatic Priority Upgrade

Individual Class 5B and 5T Eligible for automatic priority

Single OPTN Class 5A nodule

Corresponds to T1 stage HCC and does not qualify for automatic priority MELD points but must be considered towards the overall staging of the patient
Eligible for automatic priority

Combinations of Class 5A nodules that meet stage T2 criteria

For example, a candidate would be eligible for additional priority with: Two 1.5 cm (5A) lesions; or One 1.5 cm lesion (5A) and one 2.5 cm lesion (5B); or One 3.5 cm lesion (5B); or Two 2.1 cm lesions (5B)

OPTN Policies, 2013.

LI-RADS
o What is LI-RADS?
System of standardized terminology & criteria for imaging exams of liver Supported and endorsed by ACR Developed by radiologists with input from hepatobiliary surgeons, hepatologists, hepatopathologists, interventionalists LI-RADS is dynamic: will be expanded and refined as knowledge accrues

o In what patient population does LI-RADS apply?

Patients at high risk for developing HCC

o What imaging modalities are addressed by LI-RADS?

LI-RADS v2013: CT and MRI performed with extracellular contrast agents LI-RADS v2014: will be expanded to apply to hepatobiliary contrast agents

o Who can use LI-RADS?

Community and academic radiologists

o How does LI-RADS work?

LI-RADS categorizes lesions, reflecting probability of benignity or HCC
LI-RADS = Liver Imaging Reporting And Data System; ACR = American College of Radiology. American College of Radiology, version 2013.1.

LI-RADS and Possible Premalignant Lesions

Dysplastic Nodules Large Cell Dysplasia

Macroregenerative Nodules

Small Cell Dysplasia

Courtesy of Robert G. Gish, MD.

LI-RADS: Categories
LR-1 LR-2 LR-3 LR-4 Definitely benign Probably benign Intermediate probability for HCC Probably HCC

LR-5
LR-5V

Definitely HCC
Definitely HCC with Tumor in Vein

LR-M
American College of Radiology, version 2013.1.

Malignant, not necessarily HCC

LI-RADS: Algorithm
Observation in high-risk patient Treated observation Untreated observation

Definitely benign

Probably benign

Neither definitely nor probably benign

LR-Treated

LR-1

LR-2

Possible non-HCC malignancy

LR-M

Tumor in vein

LR-5V

Arterial phase hypo- or isoenhancement Diameter (mm): Washout Capsule Threshold growth < 20 20

Arterial phase hyperenhancement < 10 10-19 20

None:
One: Two:

LR-3
LR-3 LR-4

LR-3
LR-4 LR-4

LR-3
LR-4 LR-4

LR-3
LR-4 LR-5

LR-4
LR-5 LR-5

Apply ancillary features and then tie-breaking rules to adjust category

American College of Radiology.

LI-RADS and OPTN

o LI-RADS: comprehensive system. Addresses entire spectrum of lesions & pseudolesions encountered in patients at high risk for developing HCC. Includes atlas and lexicon of standardized terminology. o OPTN: focused system. Addresses definite HCC. Does not include atlas or lexicon of standardized terminology. Defers to LI-RADS all observations that do not meet imaging criteria for definite HCC. o LR-5 and OPTN5:
both indicate 100% certainty for Dx of HCC essentially equivalent (see Table next slide)
LR-5 OPTN5 LR-5 LR-5

American College of Radiology; OPTN Policies, 2013.

LR-5 and OPTN-5

LR-5 1-2cm HCC LR-5: 10-19mm Arterial phase hyper-enhancement AND 2 of following: Washout appearance Capsule appearance Threshold growth** OPTN Class 5 OPTN Class 5A: 1cm and < 2cm nodule Increased contrast enhancement on late hepatic arterial phase AND both: Washout during later contrast phases Peripheral rim enhancement (capsule/pseudocapsule) OPTN Class 5A-g: 1cm and < 2cm nodule Increased contrast enhancement on late hepatic arterial phase AND the following: Growth* OPTN Class 5B: 2cm and 5cm nodule Increased contrast enhancement on late hepatic arterial phase AND 1 of following: Washout during later contrast phases Peripheral rim enhancement (capsule/pseudocapsule) Growth* OPTN Class 5X: > 5cm nodule Increased contrast enhancement on late hepatic arterial phase AND 1 of following: Washout during later contrast phases. Peripheral rim enhancement (capsule/pseudocapsule) HCC with tumor in vein LR-5V: HCC with tumor in vein Definite enhancing soft tissue in vein Imaging criteria not provided,

2cm HCC

LR-5: 20mm Arterial phase hyper-enhancement AND 1 of following: Washout appearance Capsule appearance Threshold growth**

*OPTN requires growth by 50% or more in diameter during a greater than or equal to 6 month time interval. **LI-RADS defines threshold growth as 50% or more diameter increase during a greater then or equal to 6 month time interval Or as 100% or more diameter increase during a greater than or equal to 6 month time interval. American College of Radiology.

LR-5 and OPTN-5

o Equivalent with the following exceptions: o LR-5 uses more precisely defined terminology o LR-5 is simpler
OPTN uses -A, -B, -X designations, reflecting nodule size LI-RADS (as of 2014) omits designations (unnecessary complexity). LI-RADS requires size to be reported conversion to OPTN is easy

o 10-19mm growing arterial phase hyperenhancing nodules without washout or capsule

OPTN categorizes these as definite HCC (OPTN 5A-g) LI-RADS categorizes these as probable HCC (LR-4), because the differential diagnosis includes intrahepatic cholangiocarcinoma

o Growth assessment if imaging exams are performed 6 months apart

OPTN does not allow assessment of growth in such cases LI-RADS does allow assessment of growth in such cases

o Macrovasculoinvasive HCC
LI-RADS has LR-5V category for HCCs with tumor in vein OPTN does not have category for macrovasculoinvasive HCC
American College of Radiology.

Post-Assessment Question 1
Which of the following regarding LI-RADS is true?
1. A system of standardized terminology and criteria to interpret and report imaging examinations of the liver 2. Currently applies to patients with cirrhosis or at risk for HCC 3. Categorizes observations from LR1 to LR5, reflecting probability of benignity or HCC in at-risk patients 4. 1 and 2 only 5. 2 and 3 only 6. All of the above 7. None of the above

Current and Emerging Management of HCC:

Surgical Management, Loco-Regional Therapy, and Targeted Therapy Development

Pre-Assessment Question 2
Which of the following phase III trials did not reach its primary endpoint?
1. 2. 3. 4. 5. 6. Brivanib in the BRISK-FL trial Everolimus in the EVOLVE-1 trial Ramucirumab in the REACH trial Regorafenib in the RESORCE trial 1 and 2 only 3 and 4 only

Barcelona Clinic Liver Cancer (BCLC) Staging Classification and Treatment Schedule: proposed modifications/additions*
Hepatocellular carcinoma
(Modified from: Llovet JM et al. J Natl Cancer Inst. 2008;100:698-711.)

Stage 0 PST 0, Child-Turcotte-Pugh A

Stage A-C PST 0-2, Child-Turcotte-Pugh A or B

Stage D PST >2, Child-Turcotte-Pugh C

Very early stage (0) Single <2 cm carcinoma in situ

Early stage (A) Single nodule <5 cm or 3 nodules 3 cm, PST 0

Intermediate stage (B) Multinodular, PST 0

Advanced stage (C) Portal invasion, N1, M1, PST 1-2

Terminal stage (D)

Single

3 nodules 3 cm

Increased portal pressure and elevated bilirubin levels

Yes Associated diseases No Yes TAE or TACE Sorafenib

No

Median survival 11-20 months Resection Liver transplantation (CLT or LDLT) 5-year survival 40%-70% RFA (PEIa) *Sequence: TARE, TABE sorafenib?b *Combinations, TARE, TABE?b
a

Supportive Care Survival <3 months

Rarely used. b Confirmation required from RCTs.

HCC is Not One Disease

o Cancer and underlying liver disease o Clinically diverse cancer
physiological staging anatomical staging

o Molecularly diverse cancer

distinct molecular subtypes have begun to be identified molecular drivers still largely unknown angiogenesis is a validated target in HCC

Finn, 2010.

Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach

Hepatobiliary Surgery
Hepatology Oncology

Pathology Radiation Oncology

Guy et al, 2012.

Radiology

What We Know About Treating HCC:

o Staging patients is important
physiologic and anatomic

o The only curative approach is surgery (resection or transplant)

Most patients are not candidates for above

o Chemoembolization (TACE) and radiofrequency ablation can improve survival

In selected patients

o Eventually most patients will require systemic treatment if they live long enough o Cytotoxic chemotherapy has not had any impact on this disease o Sorafenib improves survival for patients with advanced HCC

Geographic Variations in Receipt of Potentially Curative Therapy in the Elderly Adjusting for time period, age, sex, comorbidity, liver disease severity, tumor size, risk factors for HCC
Adjusted odds ratio San Jose Utah 1.00 3.65 95% confidence interval 1.41-9.42 P-value Reference 0.008

Connecticut Detroit
Hawaii Iowa Los Angeles New Mexico San Francisco Atlanta Seattle

2.41 1.77
2.02 2.15 2.47 2.85 1.47 3.24 1.24

1.12-5.18 0.86-3.61
0.94-4.36 1.01-4.55 1.28-4.74 1.29-6.29 0.73-3.00 1.46-7.19 0.60-2.59

0.024 0.119
0.072 0.047 0.007 0.010 0.287 0.004 0.565

El-Serag et al, 2006.

Survival After Surgical Resection for HCC

Llovet et al, 1999.

Hepatic Resection
Percentage of HCCs deemed resectable at diagnosis

30% resectable

70% unresectable

Adapted from Colombo et al, 2003.

Radiofrequency Ablation
High frequency alternating current Ionic vibration & heat generation 45C: Protein denaturation 70C: Thermal coagulation 100C: Tissue desiccation
Adapted from Minami et al, 2011; Courtesy of Robert G. Gish, MD.

Early HCC Treated with RFA

o Lencioni et al, 2005: 206 patients with early stage unresectable HCC treated with RFA Favorable 5 year survival 3yr Survival Child A with single lesion 89% 5yr Survival 61%

Child A
Child B

76%
46%

51%
31%

o Tateishi et al, 2005: -1000 RFA procedures in >700 patients: -Survival: 94, 77, and 54% (1-, 3-, and 5-year)

RFA in small resectable lesions?

Lencioni et al, 2005; Tateishi et al, 2005.

Is RFA Better Than Surgical Resection? Surgery considered better, but...

148 patients Child A; case control RFA vs. Surgical resection 1yr Survival
Surgery (N=93) RFA (N=55)

3yr Survival
83.9% 72.7%
P=0.24

Recurrence
45.2% 58.2%
P=0.54

97.9% 100.0%

o Overall survival + recurrence-free survival: RFA = surgical resection for single small HCC with good hepatic reserve o Rate of local recurrence: RFA > surgical resection
Hong et al, 2005.

Treatment: Chemoembolization
o Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery o Tumor receives most of its blood supply from the hepatic artery o Injection into the hepatic artery spares most of the normal liver o Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor
Tumor
Catheter placement for chemoembolization

Hepatic artery

Liver
Portal vein

Ramsey et al, 2004.

Chemoembolization: Randomized Trials (Nearly Identical Techniques)

Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal) Technique
TACE Supportive care

Year 1 57 32

Survival, % Year 2 31 11

Year 3 26 3

Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal)
Technique TACE Supportive care Survival, % Year 1 82 63 Year 2 63 27

HBV = hepatitis B virus; HCV = hepatitis C virus; TACE = transcatheter arterial chemoembolization. Lo et al, 2002; Llovet et al, 2002.

Largest Prospective Study of TACE for Unresectable HCC to Date

o N = 8510 patients o Primary endpoint: OS o Multivariate analysis conducted for factors affecting survival o OS
Year 1: 82%; Year 3: 47%; Year 5: 26%; Year 7: 16% OS better with lesser degree of liver damage

o Factors affecting survival

Child-Pugh stage TNM stage (OS better with stage I, increasingly worse progressing toward stage IV) Alpha-fetoprotein level
OS = overall survival; TACE = transcatheter arterial chemoembolization; TNM = tumor, node, metastasis. Takayasu et al, 2006.

TACE vs Surgical Resection: A Case-Control Prospective Study

N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors < 3 cm
Technique TACE Survival, % Year 1 96 90 Year 2 80 80 Year 3 56 70 Year 5 30 52

Surgical resection

o Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0
BUT for tumors > 3 cm and/or CLIP stage 1-2, 5-year survival identical for both groups (27%)

o Median OS (P = .1529)
o Resection: 65.1 months o TACE: 50.4 months
CLIP = Cancer of the Liver Italian Program; HBV = hepatitis B virus; TACE = transcatheter arterial chemoembolization. Lee et al, 2002.

Response to TACE as a Biological Selection Criterion for LT in HCC

1.0 0.8 Survival 0.6 0.4 0.2 0 0 365 730 1095 1460 1825 All patients 51.9% TACE nonresponders 0% Transplanted 80.9%

o Overall 5-year survival: 51.9%

Highly significant difference in 5-year survival between downstaged (transplanted) patients and patients not responding to TACE (P < .0001)

o Survival calculated from the beginning of TACE treatment

Days
LT = liver transplantation; TACE = transcatheter arterial chemoembolization. Otto et al, 2006.

Response to TACE as a Biological Selection Criterion for LT in HCC

1.0 Freedom From Recurrence 94.5%

0.8
P = .0017 0.6 0.4 35.4% 0.2 0 0 TACE responders TACE nonresponders

365

730 1095 Days

1460

1825

LT = liver transplantation; TACE = transcatheter arterial chemoembolization. Otto et al, 2006.

Results
o Dose:
Main PVT were treated with > 1 cycle (p = 0.0296 with cirrhosis; p = 0.0077 without cirrhosis) No significant difference in the median first dose or accumulated radiation dose (Gy)

Adverse Events:
Cirrhosis No PVT N =52 N (%) Branch PVT N = 19 N (%) Bilirubin Ascites HE 18 (35) 8 (15) 2 (4) 8 (42) 1 (5) 1 (5) Main PVT N =11 N (%) 7 (64) 6 (55) 0 0.2003 0.0042 1.0000 P value

o Tumor Response:
WHO criteria: 42.2% EASL (necrosis >50%): 70% Stable Disease: 34.7% Progression: 23.1%
Without Cirrhosis No PVT Branch Main P value

N =19
N (%)

PVT
N =6 (N %)

PVT
N =1 N (%)

Bilirubin
Ascites HE

1 (5)
0 0

0
1 (17) 0

0
0 0

1.0000
0.2692 -

EASL = European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; PVT = portal vein thrombosis; WHO = World Health Organization. Kulik et al, 2008.

Intra-arterial Radioembolization With Yttrium-90: Rationale and History

o Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors o Yttrium-90 microspheres Average diameter: 20-30 m 100% pure beta emitter (0.9367 MeV) Physical half-life: 64.2 hours Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm)

Murthy et al, 2006.

Yttrium-90 Radiotherapy for HCC Patients With and Without PVT

o Phase II study: N = 108 (37 with PVT, 71 without PVT)

o Stratified by toxicity: Child-Pugh score (in cirrhotics), dose, location of PVT

o Median dose: 134 Gy

o Partial response rate: 42% (WHO), 70% (EASL)

o Adverse event rate highest in patients with main PVT and cirrhosis o Median survival, main PVT: 133.5 days
Branch PVT: 304 days No PVT: 467 days
EASL = European Association for the Study of the Liver; WHO = World Health Organization; PVT = portal vein thrombosis. Kulik et al, 2008.

PRECISION TACE with DC Bead Addressing the challenge of improved survival in hepatocellular carcinoma

Courtesy of Dr. David Brophy, St. Vincents University Hospital, 2013.

Assessing Response in HCC

WHO Complete Response (CR) Partial Response (PR) Stable Disease (SD) Disappearance of lesion(s) 50% decrease Neither PR or PD RECIST Disappearance of lesion(s) 30% decrease SD Neither PR or PD PD Progressive Disease (PD) 25% increase; no CR,PR or SD documented before increase 20% increase; no CR,PR or SD documented before increase 25% increase of arterial enhancement CR EASL Criteria Disappearance of intratumoral arterial enhancement 50% decrease of arterial enhancement Neither PR or PD

PR

Therasse et al, 2000; Bruix et al, 2001.

Milan Criteria
1 lesion < 5 cm

3 lesions, none > 3 cm

o No evidence of extrahepatic spread o Based on pre-transplant imaging o 4 year survival 74% o Recurrence rate <10% o Validated in several studies with > 1000 patients
5 yr survival >70% Recurrence < 15%

Mazzaferro et al, 1996.

Cumulative Recurrence Rate

50

Recurrence (%)

40
Milan No (n=172)

30 20 10 0 0 1 2 3

Milan Yes (n=137)

Post transplant years

Todo et al, 2004.

Current MELD Upgrade for HCC

o Patients outside Milan criteria
Listed without MELD upgrade Transplanted at discretion of individual transplant centers on patients calculated MELD

o Patients downstaged with liver directed therapy

Special case to the Regional Review Board (RRB) for MELD upgrade to 22 with upgrade q 3 months as a special case

MELD = Model for End-Stage Liver Disease. Kamath et al, 2007.

UCLA Experience: 467 HCC Patients

Survival estimate by preoperative imaging assessment Survival estimate by pathologic explant examination (n=126)

(n=173)

86% 71%
(n=208)

79%
(n=185)

64%

(n=109)

41%
(n=133)

32%

Duffy et al, 2007.

Molecular Targeted Therapies Assessed in Phase II Clinical Trials in HCC

Adapted from Shin et al, 2013 and Zhu, 2013.

Phase III SHARP Trial: Overall Survival Intent-to-Treat Population

1.00 sorafenib Median: 46.3 weeks (10.7 months) (95% CI, 40.9-57.9) Placebo Median: 34.4 weeks (7.9 months) (95% CI, 29.4-39.4) Survival Probability 0.75

0.50

0.25 Hazard ratio in sorafenib group: 0.69 (95% CI, 0.55-0.87) P=0.00058* 0 8
274 276

16
241 224

24
205 179

Patients at risk sorafenib 299 placebo 303

Llovet et al, 2008.

32 40 48 Time (weeks)
161 126 108 78 67 47

56
38 25

64
12 7

72
0 2

80

*OBrien-Fleming threshold for statistical significance was P=0.0077.

Phase III SHARP Trial: Time to Tumor Progression (Independent Review)

1.00
Progression -Free Probability sorafenib Median: 24.0 weeks (5.5 months) (95% CI, 18.0 30.0) Placebo Median: 12.3 weeks (2.8 months) (95% CI, 11.7 17.1)

0.75

0.50

0.25

Hazard ratio: 0.58 (95% CI, 0.45 0.74) P=0.000007

0 0 6
196 192

12
126 101

18
80 57

Patients at risk sorafenib : 299 Placebo: 303

Llovet et al, 2008.

24 30 36 Time (weeks)
50 31 28 12 14 8

42
8 2

48
2 1

54

Phase III SHARP Trial: Best Response by RECIST (Independent Review)

sorafenib n=299 % Overall response Complete response 0 0 Placebo n=303 %

Partial response
Stable disease

2
71

1
67

Progressive disease
Progression-free rate at 4 mo

18
62

24
42

*Not assessable: sorafenib (8.7%), placebo (8.3%). RECIST=Response Evaluation Criteria in Solid Tumors. Llovet et al, 2008.

Phase II SPACE Trial: Sorafenib or Placebo in Combination With TACE for Intermediate-Stage HCC
o Phase 2, randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with TACE with DEBDOX for intermediate-stage HCC
Selected Eligibility Criteria
R A N D O M I Z E 1:1 (n = 307)

Primary Endpoint
TTP TACE with DEBDOX + sorafenib 400 mg bid TACE with DEBDOX + placebo

Unresectable HCC Multinodular HCC Child-Pugh A without ascites or encephalopathy ECOG PS 0

Secondary Endpoints

EHS/MVI Contraindication to TACE

Selected Exclusion Criteria

OS Safety Time to untreatable progression Time to vascular invasion/EHS Biomarker analysis Patient-reported outcomes

TACE = transarterial chemoembolization; DEBDOX = doxorubicin-eluting beads; EHS = extrahepatic spread; MVI = macroscopic vascular invasion; TTP = time to radiologic progression. Lencioni et al, 2012.

Phase II SPACE Trial: Results

o 307 were randomized
Sorafenib (n=154) placebo (n=153)

o o

Median TTP (50th percentile) was 169 days in the sorafenib group; 166 days in the placebo groups TTP at the 25th and 75th percentiles (preplanned) was 112/88 days and 285/224 days in the sorafenib and placebo groups, respectively

Assessment *
HR 95% CI P value (1sided)**

TTP

OS***

Time to VI/EHS***
0.621 0.321, 1.200 0.076

TTUP

0.797 0.588, 1.080 0.072

0.898 0.606, 1.330 0.295

1.586 1.200, 2.096 0.999

* = ITT population (all randomized patients; ** = predefined alpha = 0.15; *** = median was not reached in either group. EHS = extrahepatic spread; VI = vascular invasion; TTP = time to radiologic progression; TTUP = time to untreatable progression. Lencioni et al, 2012.

Unmet Needs in Advanced HCC

o First-line therapies that improve clinical outcomes relative to treatment with sorafenib (the standard of care)1,2 with regard to
efficacy1 safety and tolerability1
(options also needed for patients who are ineligible)

quality of life (QoL)3

o Second-line therapies for patients who progress on or do not tolerate sorafenib1

What is the natural history of this population after sorafenib?

1. Finn et al, 2010; 2. Llovet et al, 2008; 3. Fan et al, 2010.

Phase III Trials of First-Line Therapy in Advanced HCC

Study drug (trial acronym) Sorafenib + doxorubicin (CALGB-80802)1 Sorafenib + erlotinib (SEARCH)2 Linifanib3 Brivanib (BRISK-FL)4 Sunitinib5 Lenvatinib6 Mechanism Sorafenib: multikinase inhibitor (VEGFR, PDGFR, Raf, others) Doxorubicin: cytotoxic Sorafenib: multikinase inhibitor (VEGFR, PDGFR, Raf, others) Erlotinib: RTKI of EGFR-1 Multikinase inhibitor (VEGFR, PDGFR, others) Selective inhibitor of FGFR + VEGFR Oral multitargeted tyrosine kinase inhibitor Multikinase inhibitor of (VEGFR, FGFR, others) Sorafenib Sorafenib 1035 1050 OS OS negative negative negative 2015 Sorafenib 720 OS negative Control Sorafenib N 480 Primary Data endpoint expected OS On hold

Sorafenib
Sorafenib

1075
940

OS
OS

1 NCT01015833; 2

NCT00901901; 3 NCT01009593; 4 NCT00858871; 5 NCT00699374; 6 NCT01761266.

Linifanib: Who benefited? What are predictive markers? Study M06-879: 1st or 2nd Line Advanced HCC Best Percentage Change from Baseline in Target Lesions

Endpoints Primary PFR at 16 Weeks % [95% CI] Secondary TTPra, median mo [95% CI] OS, median mo [95% CI] ORR % [95% CI]

All Patients n=44 31.8 [18.6, 47.6] 5.4 [3.6, 7.3] 9.7 [6.4, 12.2] 9.1 [2.5, 21.7]

Child-Pugh A n=38 34.2 [19.6, 51.4] 5.4 [3.6, 9.2] 10.4 [8.4, 14.3] 10.5 [2.9, 24.8]

Child-Pugh B n=6 16.7 [0.4, 64.1] NR [3.7, NR] 2.5 [1.0, 4.5] 0

aRadiographic

progression only. Data available August 2010. Responses confirmed on 2 visits>4 weeks apart.

*Per Central Imaging

Toh et al, 2013. NR = not reached; ORR = objective response rate; OS = overall survival; PFR = progression-free rate; TTP = time to disease progression; TTPr = time to disease progression-radiographic.

Phase III Trials of Second-Line Therapy in Advanced HCC

Study drug (trial acronym) Brivanib (BRISK-PS)1 Everolimus (EVOLVE-1)2 Ramucirumab (REACH)3 Brivanib (BRISK-APS)4 Tivantinib (METIV-HCC)5 Regorafenib (RESORCE)6 Cabozantinib VEGFR inhibitor Placebo 530 OS 2016 cMET inhibitor Placebo 303 OS 2014 Mechanism Selective inhibitor of FGFR + VEGFR mTOR inhibitor MAb to VEGFR-2 Selective inhibitor of FGFR + VEGFR Control N Primary endpoint OS OS OS OS Data expected Negative Placebo Placebo Placebo Placebo 395 546 544 252

Negative 2014 2014

(CELESTIAL)7
ADI-PEG-208

cMET, VEGFR2, RET

Arginine-deiminase

Placebo
Placebo

760
633

OS
OS

2016
2014

1 7

Llovet et al, 2012; 2 Zhu et al, 2014; 3 NCT01140347; 4 NCT01108705; 5 NCT01755767; 6 NCT01774344; NCT01908426; 8 NCT01287585.

BRISK-PS: Decreased Time to Progression (but no change in survival: data not shown)
1.0 0.8

Probability of Progression

0.6 Brivanib 0.4 Placebo

Events / patients Median TTP, mo HR (95% CI)

151 / 263 4.2 0.0001

75 / 132 2.7

0.56 (0.42 0.78)

0.2

P (log rank)

0.0 0 2 4 6 8 10 12 Months
Number of Patients at Risk Brivanib 263 144 Placebo 132 45
Llovet et al, 2012.

14

16

18

20

22

24

92 21

37 6

20 5

9 2

3 1

2 1

1 1

0 1

0 1

0 1

0 0

Brivanib: Can We Find the Subset of Patients Who Will Benefit? Change in Target Tumor from Baseline
Maximum Tumor Change from Baseline (%) Brivanib N = 210 Placebo N = 101

Patients with both baseline and on-study tumor assessment, N = 311

Llovet et al, 2012.

Ramucirumab
o VEGFR-2 and its ligands (including VEGF-A, -C, and -D) are important mediators of angiogenesis and angiogenesis is integral to HCC carcinogenesis and pathogenesis o Ramucirumab is a recombinant human monoclonal antibody (MAb) of the immunoglobulin G, subclass 1 (IgG1) that binds to the extracellular domain of VEGFR-2 with high specificity and affinity o Ramucirumab was well tolerated in 2 Phase 1 studies involving patients with advanced, refractory solid tumors; and 2 HCC patients (receiving doses of 10 mg/kg Q2W) had disease stabilization on-study for 9 and 14 months, respectively
VEGFR-2 = vascular endothelial growth factor receptor 2. Zhu et al, 2010.

Best Overall Response and Objective Response Rate

n
Best Overall Response
Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) Not Evaluable (NE) Objective Response Rate Response Rate (CR + PR) 95% CI Dis. Control Rate (SD + RR) 95% CI 9.5% (3%-23%) 69% (53%-82%) 0 4 25 9 4 (0%) (10%) (60%) (21%) (10%)

(%)

Zhu et al, 2013.

Ramucirumab: CP12-0710 Overall Survival

All Patients BCLC C

Child A Child B

All Patients OS Median 95% CI 1 year OS Rate 95% CI

Zhu et al, 2013.

BCLC C - Child A 18.0 6.1-23.5

BCLC C - Child B 4.4 0.5-9.0

12.0 6.1-19.7 49.4% 33.1-63.7

HGF/ c-MET and HCC

o HGF/ cMET signaling plays a role in liver regeneration1 o cMET expression is reported increased in HCC2,3,4
Prognostic value is unclear

o HGF expression and cMET activation in models can induce tumor growth5
HGF expression reported to be decreased in HCC

o cMET overexpression by IHC correlates with poor prognostic features and poor outcomes6,7,8 o Elevated plasma HGF associated with decreased benefit to sorafenib in SHARP9
HGF = hepatocyte growth factor; ICH = immunohistochemistry 1. Borowiak et al, 2004; 2. Kiss et al, 1997; 3. Selden et al, 1994; 4.Tavian et al, 2000; 5. Horiguchi et al, 2002; 6. Ueki et al, 1997; 7. Wu et al, 2006; 8. Rimassa et al, 2012; 9. Lovett et al, 2012.

Improved OS in MET Diagnostic High Group

Rimassa et al, 2012; Santoro et al, 2013.

Conclusions
o Molecular targeted therapeutics will play a role in the future of HCC management o Sorafenib has established a benchmark for front-line studies o Great unmet need for patients who are ineligible for, intolerant to, and who progress on sorafenib o Integrating new clinical assessment tools into clinical trials o Randomized Phase II trials are needed to better assess activity for moving agents into Phase III o Identify promising new targets for therapy
better identify patients who will receive benefit

Optimizing Multidisciplinary Management of HCC

Current standard
Interv. radiology Hepatology Surgery Oncology Pathology

Treatment decision What we want Patient call

Treatment

All relevant specialists Treatment decision Patient communication

Courtesy of Carrie Frenette, MD, CPMC integrated HCC clinic.

Post-Assessment Question 2
Which of the following phase III trials did not reach its primary endpoint?
1. 2. 3. 4. 5. 6. Brivanib in the BRISK-FL trial Everolimus in the EVOLVE-1 trial Ramucirumab in the REACH trial Regorafenib in the RESORCE trial 1 and 2 only 3 and 4 only

Practical Application Cases

Case Study 1
o 65 year old Asian man
Chronic HBV treated with tenofovir No decompensation (MELD 6) Good functional status

o HCC screening
CT: 2.6 cm (S6) enhancing mass with PV washout AFP 15 ng/ml

o Referred for evaluation

HBV = hepatitis B virus; MELD = model for end-stage liver disease; PV = portal venous; AFP = alfa-fetoprotein.

Case Study 1 (cont.)

o PE: anicteric, no stigmata
Liver / spleen not palpable, no ascites No hepatic bruit

o Lab: bili 0.5, AP 75, AST 45 ALT 63

WBC 3.9 Hgb 16.5 PLT 189 PT 10.4 sec (INR 0.9)

Case Study 1: Imaging

3/13/1952 59 YEAR M A C T ABDOMEN \T\ PELVIS W \T\ W/O C ONT ARTERIAL 9/13/2011 3:17:26 PM 790477 APPLIED LOC : -1081 THK: 2 FFS
3/13/1952 59 YEAR M A C T ABDOMEN \T\ PELVIS W \T\ W/O C ONT VENOUS 9/13/2011 3:17:54 PM 790477 APPLIED LOC : -1093 THK: 2 FFS

RD: 402 Tilt: 0 mA: 366 KVp: 120 Acq no: 13 Page: 112 of 768 P

Z: 1 C : 40 W: 400 DFOV:40.2x40.2cm C ompressed 11:1 IM: 26 SE: 7 cm

RD: 402 Tilt: 0 mA: 297 KVp: 120 Acq no: 14 Page: 217 of 768 P

Z: 1 C : 40 W: 400 DFOV:40.2x40.2cm C ompressed 11:1 IM: 21 SE: 8 cm

arterial phase

portal venous phase

Case Study 1: CT / angiography showed a second lesion in the left lobe

Case Study 1 (cont.) now with two lesions

o More investigation ?
AFP-L3 Lesion biopsy

o Ablation ? Bridge to surgery or transplant?

PEI RFA TACE

o Primary resection
chemo-prevention

o MELD exemption / OLTx ?

PEI = percutaneous ethanol injection; RFA = radiofrequency ablation; TACE = transcatheter arterial chemoembolization; MELD = model for end-stage liver disease; OLTx = orthotopic liver transplantation.

Case Study 1 (continued)

o Options
Primary resection Liver replacement? RFA alone TACE alone RFA + TACE

o Chemo-prevention after treatment if no OLTx?

Case Study 2: Patient during a Follow-up visit 5 Years After Diagnosis of HCV
o 5 years after your initial evaluation for HCV genotype1, patient declined INF based therapies historically, at age 40, the patient presents with abdominal fullness, a 5-lb weight loss, and fatigue o Laboratory tests Albumin: 3.0 g/dL INR: 1.5 Bilirubin: 3 mg/dL ECOG PS 1

HCV = hepatitis C virus; INF = interferon; INR = international normalized ratio; Eastern Cooperative Oncology Group Performance Status.

Case Study 2: CT Scan Performed

o A 4-phase CT scan reveals a 7-cm lesion placed between segment 1 and 4 near the portal vein with classic arterial uptake and rapid washout consistent with HCC o Ascites was seen surrounding the liver and a small amount in the pelvis

Case Study 2 (cont.)

Question 1
What is the best next step to treat this patient?
a) b) c) d) e) f) g) TACE RFA Liver transplantation IV doxorubicin Yttrium-90 microspheres Oral therapy with a multitargeted TKI Other

TKI = tyrosine kinase inhibitor.

Case Study 2: Decision

o You decide to initiate treatment with TACE

Case Study 2: Evolution

o 5 weeks later, a 4-phase CT is performed and shows no residual lipiodol, and now the tumor is 8 cm without evidence of significant necrosis

Question 2
What is the best next step to treat this patient?
a) b) c) d) e) f) g) TACE RFA Liver transplantation IV doxorubicin Yttrium-90 microspheres Oral therapy with a multitargeted TKI sorafenib Other

Case Study 2: Decision

o You decide to initiate treatment with sorafenib

Question 3
What is the optimal sorafenib dosage for this patient?
a) 100 mg orally twice daily b) 200 mg orally twice daily c) 400 mg orally twice daily

Case Study 2: Decision and Evolution

o The patient was started on sorafenib 400 mg orally twice daily taken without food o After sorafenib therapy was started, a painful red palmar rash developed 2 weeks after starting therapy o This was scored as a grade 2 reaction

Case Study 2: Multitargeted TKI Toxicity: Hand-Foot Skin Reaction

o More than 90% of patients experience skin reactions on multitargeted TKI therapy
Incidence of hand-foot skin reaction reported as high as 60%
21% in SHARP trial (all grades)

Yang et al, 2008; Autier et al, 2008; Llovet et al, 2008.

Question 4
What is the next best step for treatment?
a) Immediate sorafenib discontinuation plus supportive care to address skin reaction b) Sorafenib dose interruption for 1 week plus supportive care c) Sorafenib dose reduction by 50% plus supportive care d) Sorafenib dose reduction by 75% plus supportive care e) Use supportive care to address skin reaction; alter dose after 1 week if no improvement

Question 5
What therapies would you initiate before starting sorafenib?
a) b) c) d) e) f) Loperamide hydrochloride Vitamin B6 Hydrocodone bitartrate Dolasetron mesylate Other None

Question 6
What HCV therapies would you consider before or after starting sorafenib?
a) b) c) d) e) f) INF + ribavirin SOF + ribavirin for 24 weeks INF + ribavirin + SOF INF + ribavirin + SIM SOF + SIM None

INF = interferon; SOF = sofosbuvir; SIM = simeprevir.

Case Study 2: Progression Question 7

o The patient progresses after sorafenib Which of the following would be an acceptable treatment option? a) Ramucirumab in a clinical trial b) Brivanib in a clinical trial c) Regorafenib in a clinical trial d) All of the above

Audience Q&A

Thank You
o Thank you for participating in this activity, Advanced Hepatocellular Carcinoma: Management Strategies for Emerging Targeted Therapies o Enduring Activity:
Downloadable Slide Deck and accompanying speaker notes for use as a self-study resource to assist in reinforcing key learning points from this live activity or for you to incorporate into additional staff education.

o Please email: 1225" in the subject line to: optin@AXISMedEd.com o You will be provided a link in which to access and download these supplemental educational resources.

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