disclosures participated in the following advisory boards: gilead hoffman la roche janssen merck...
TRANSCRIPT
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