1. Supported by Bayer HealthCare and Onyx Pharmaceuticals
Sorafenib Improves Survival in Hepatocellular Carcinoma: Results of a Phase III Randomized, Placebo-Controlled Trial
Josep M. Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Jean-Luc Raoul, Stefan Zeuzem, Armando Santoro, Minghua Shan, Marius Moscovici, Dimitris Voliotis, and Jordi Bruix, for the SHARP Investigators Study Group
Supported by Bayer HealthCare and Onyx Pharmaceuticals

2. Epidemiology of HCC Fifth most common cancer globally1
Over 600,000 new cases of liver cancer are diagnosed globally each year1
Eastern Asia: 370,0001
Japan: 40,0001
Europe: 32,0002
United States: 19,0003
HCC is the third leading cause of cancer-related mortality,1 and is the leading cause of death in cirrhotic patients
The incidence of HCC is increasing globally4
Available systemic therapies have no proven survival advantage
1. International Agency for Cancer Research. GLOBOCAN Available at: Accessed April 23, 2007.
2. International Agency for Cancer Research. EUCAN Available at: Accessed April 26, 2007; 3. Jemal A et al. CA Cancer J Clin. 2007;57:43-66; 4. Bosch XF et al. Clin Liver Dis. 2005;9:

3. Rationale HCC treatment schedule
Early Stage
Intermediate Stage
Advanced Stage
End Stage
Surgical Treatments
Local Ablation
TACE
New Agents
(30%)
Potentially curative treatments
5-yr survival: 50-70%
(50-60%)
Randomized trials
median survival if untreated: 6-16 mo
(10%)
BSC
survival <3 mo
Llovet JM, & Bruix J, BCLC. Lancet, 2003 5 5

4. Sorafenib in HCC: Rationale
Raf kinase is overexpressed and activated in HCC1
RAF/MEK/ERK signaling pathway is implicated in liver tumorigenesis1-3
Sorafenib, approved in advanced RCC, is the only approved inhibitor of Raf kinase4
Sorafenib is a multikinase inhibitor of RAF, VEGFR, and other kinases3
Sorafenib induces apoptosis in HCC xenograft models4
Sorafenib was active in a Phase II trial of patients with advanced HCC and Child-Pugh class A and B liver function status5
1. Hwang et al. Hepatol Res. 2. Calvisi et al, Gastroenterology 2006
3. Villanueva et al. Sem Liv Dis Liu et al. Cancer Res Abou-Alfa et al. J Clin Oncol

5. Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis
Endothelial cell or Pericyte
Autocrine loop
EGF/HGF
Paracrine
stimulation
PDGF-b
VEGF
PDGFR-b
VEGFR-2
Apoptosis
RAS
RAS
RAF
RAF
Sorafenib
Sorafenib
Mitochondria
MEK
Mitochondria
MEK
Angiogenesis:
HIF-2
ERK
EGF/HGF
Apoptosis
Differentiation
Proliferation
Migration
Tubule formation
ERK
PDGF
Nucleus
VEGF
Nucleus
Proliferation
Survival
Wilhelm S et al. Cancer Res. 2004;64:

6. Phase III SHARP Trial Study design
Primary end-points: Overall survival
Time to symptomatic progression (FHSI8-TSP)
Secondary end-points: Time to progression (independent review)
Sorafenib (n=299)
400 mg po bid
continuous dosing
Stratification:
Macroscopic vascular
invasion and/or
extrahepatic spread
ECOG PS
Geographical region
Randomization
N=602
Placebo (n=303)
2 tablets po bid
continuous dosing

7. Phase III SHARP Trial Study design
International, multicentre Phase III study
Inclusion criteria:
Histology-proven HCC
Advanced HCC
At least 1 measurable untreated lesion
ECOG 0-2
Child-Pugh A class
No prior systemic treatment
Randomization
Double-blind sorafenib 400 mg bid vs placebo; ratio 1:1
Accrual: March 2005 to April 2006 2 2

8. Phase III SHARP Trial Study design
Treatment schedule
Sorafenib 400 mg bid continuous dosing until:
Both radiologic progression and FHSI8-TSP were achieved
Any adverse event requiring discontinuation
Statistical methods
Intention-to-treat analysis
Sample size: N=560 patients (424 OS events)
Overall alpha for trial maintained at =0.025 (one-sided)
Overall survival assessment
=0.02 (one-sided)
Two interim analyses planned using O’Brien-Fleming  spending function
90% power to detect a 40% improvement: 7 months → 9.7 months
TTSP assessment (FHSI8-TSP)
=0.005 (one-sided)
Single analysis performed at time of final survival analysis 2 2

9. Phase III SHARP Trial Summary of trial conduct
2nd Interim analysis OS
Events: 321 deaths
Date: Oct 17th, 2006
Sorafenib (n=299)
Placebo (n=303)
902 patients with HCC screened
602 pts randomized
Consent withdrawn: 8%
Death: 4%
Adverse events: 5%
Protocol deviations: 83%
2 did not receive treatment
1 did not receive treatment
DMC recomendación
Stop RCT 5 7 5

10. Baseline characteristics of patients
Sorafenib
(n=299)
Placebo (n=303)
Age (yr, median) 65 66
Male/Female (%)
87/13
Region (Europe/N. America/other; %)
88/9/3
87/10/3
Etiology
Viral hepatitis (HCV/HBV)
Alcohol/other
29/19
26/26
27/18
26/29
Child-Pugh (A/B; %)
95/5
98/2
Prior therapies: Surgical resection
Loco-regional therapies
19%
39%
21%
41% 4 4

11. Baseline characteristics of patients
Sorafenib
(n=299)
Placebo
(n=303)
BCLC stage (%) Stage B Stage C
18 82
17 83
ECOG PS (%) ECOG 0 ECOG 1 ECOG 2
Vascular invasion / extrahepatic spread Present Absent
70 30 4 4

12. Phase III SHARP Trial Overall survival (Intention-to-treat)
1.00
0.75
0.50
0.25
Sorafenib Median: 46.3 weeks (95% CI: 40.9, 57.9)
Placebo Median: 34.4 weeks (95% CI: 29.4, 39.4)
Survival Probability
Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88)
P= * 8 16 24 32 40 48 56 64 72 80
Weeks
274
241
205
161
108 67 38 12
Patients at risk Sorafenib:
276
224
179
126 78 47 25 7 2
Placebo:
299
303
*O’Brien-Fleming threshold for statistical significance was P=

13. Phase III SHARP Trial Time to progression (Independent central review)
1.00
0.75
0.50
0.25
Sorafenib Median: 24.0 weeks (95% CI: 18.0, 30.0)
Probability of Progression
Placebo Median: 12.3 weeks (95% CI: 11.7, 17.1)
Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74) P= 54 6 12 18 24 30 36 42 48
Weeks
Patients at risk Sorafenib:
299
196
126 80 50 28 14 8 2
192
101 57 31 12 1
Placebo:
303

14. Phase III SHARP Trial Response assessment (RECIST; Independent review) Time to symptom progression (FSHI8-TSP)
Sorafenib (n=299)
Placebo (n=303)
Overall response
Complete response (CR) Partial response (PR)
0 7 (2.3%)
0 2 (0.7%)
Stable disease (SD)
211 (71%)
204 (67%)
Progressive disease
54 (71%)
73 (24%)
Progression-free rate at 4 mo
62 %
42 %
Duration of treatment (median, weeks) 23 19
FSHI8-TSP: No significant differences between treatment groups (P=0.77).

15. Phase III SHARP Trial Exploratory subgroup analysis
Sorafenib benefit
Placebo benefit
ECOG PS 0
ECOG PS 1 & 2
Macroscopic vascular invasion
No macroscopic vascular invasion
No macroscopic VI/extrahepatic spread
Macroscopic VI/extrahepatic spread
No extrahepatic spread
Extrahepatic spread
0.5
1.0
1.5
0.0
Hazard Ratio

16. Safety events Sorafenib (n=297) Placebo (n=302)
Treatment-emergent serious adverse events (SAE, %) 52 54
Drug-related adverse events (%) 13 9
Drug-related adverse events (%)
All
Grade 3/4
Diarrhea 39 8 11 2
Pain (abdomen) 3
<1
Weight loss 9
Anorexia 14
Nausea 1
Hand-foot skin reaction 21
Vomiting 5
Alpecia
Liver dysfunction
Bleeding 7 4
<1/ <1 4 4

17. Phase III SHARP Trial Conclusions
Sorafenib prolonged overall survival vs placebo in advanced HCC
Median OS, 46 weeks vs 34 weeks
HR 0.69, P=
44% increase in overall survival
Sorafenib prolonged time to progression vs placebo
Median TTP, 24 weeks vs 12 weeks
HR 0.58, P=
73% prolongation in time to progression
Sorafenib was well-tolerated with manageable side effects
Changes
Michael Shan: Added medians and HRs
Jeff Humphrey/Susan Kelley/Rita: Added 44% increase in OS
Lisa Melilli: Changed FHSI-TSP statement to her exact wording
Points to Consider
Should we add % improvement in TTP?
Marius: add “clinically meaningful” to 1st bullet
Howard Snow: add bullet that safety was consistent with TARGETs

18. Phase III SHARP Trial Conclusions
Sorafenib is the first systemic therapy to prolong survival in HCC patients
Sorafenib is the new reference standard for systemic therapy of HCC patients
Changes
Susan Kelley/Robert Rosen: Added bullet to tie in MOA story
Dimitris: Changed final bullet from “first-line” from “first-systemic
Dimitris: Added subbullet on sorafenib clinical benefit in HCC
Points to Consider
1. Jim Partyka: 3rd bullet somewhat overstepping. Consider instead “this study demonstrates that sorafenib is safe and effective in the first-line treatment of HCC”

19. SHARP trial acknowledgments
Italy: Dino Amadori, Francesco Cognetti, Antonio Craxi, Fabio Farinati, Cesare Gridelli, Luigi Bolondi, Angelo Sangiovanni, Andrea Martoni, Camillo Porta, Armando Santoro, Franco Trevisani, Vincenzo Mazzaferro, Sergio Ricci Poland: Jacek Jassem, Grazyna Rydzewska, Andrzej Szawlowski, Piotr Tomczak Romania: Stefan Curescu, Lucian Miron, Florinel Badulescu Russia: Eskender Topuzov, Alexei Chzhao, Vladislav Novozhenov, Pavel Bogomolov, Valery Kubyshkin Spain: Jordi Bruix, Javier Bustamante Schneider, José Luís Montero Alvarez, Moises Diago, Cristina Grávalos, Luís Ruíz del Arbol, Bruno Sangro, Ricard Solá, Josep Tabernero, Sonia Pascual Switzerland: Beat Muellhaupt, Arnaud Roth United Kingdom: Tim Meyer, T. R. Jeffry Evans, Stephen Falk, Helen Reeves, Paul Ross
Canada: Morris Sherman, Charles Olweny, Kelly Burak, Rakesh Goel, Mang Ma, Peter Metrakos United States: Carolyn Britten, Nashat Gabrail, Philip Gold, Peter Kennedy, Jorge Marrero, Alex Befeler, Thomas Boyer, Douglas Heuman, Samuel So, Josep Llovet, Alvaro Koch, Michael Schilsky, Rise Stribling, Alec Goldenberg, Thomas Byrne, Stuart Gordon, Jonathan Schwartz, Brian Carr, Guadalupe Garcia-Tsao
Belgium: Ivan Borbath, Jean-Luc Van Laethem, Hans Van Vlierberghe, Jacques De Greve, Werner Van Steenbergen Bulgaria: Iskren Kotzev, Dimitar Takov, Konstantin Tchernev France: Michel Beaugrand, Jaafar Bennouna, Jean-Pierre Bronowicki, Françoise Degos, Sophie Dominguez, Jean-Didier Grange, Patrick Hillon, Jean-Luc Raoul, Jean-François Seitz, Jean-Frédéric Blanc Germany: Hubert Blum, Wolfgang Caspary, Peter Buggisch, Reiner Wiest, Mathias Dollinger, Guido Gerken, Burkhard Göke, Michael Gregor, Tim Greten, Dieter Häussinger, Peter Galle, Johann Scherübl, Roland Schmid, Ulrich Spengler, Gerhard Treiber, Stefan Zeuzem, Max Scheulen Greece: Constantin Arvanitakis, Georgios Germanidis, Ioannis Katsos, Israel: Salomon Stemmer, Arie Figer, Ron Epelbaum
Argentina: Maria Guadalupe Pallota, Juan Jose Zarba, Marcelo Silva Brazil: Carlos Barrios, Andre Cosme de Oliveira Chile: Jorge Martinez-Castillo, Claudia Gamargo Garate Mexico: Laura Estela Cisnero Garza, Jesus Miguel Lazaro Leon Peru: Jorge Leon, Adelina Lozano
The patients and their families
Australia: Michael Boyer, Benjamin Thomson, Howard Gurney, Stephen Riordan, Niall Tebbutt, Andrew Strickland New Zealand: Edward Gane, Anne O'Donnell