1. Hepatocellular Carcinoma: Progress at last Alan P. Venook, M.D. University of California, San Francisco

2. Sorafenib in HCC Sorafenib in HCV patients: subset analysis Bolondi et al for SHARP Doxorubicin +/- sorafenib: randomized ph II Abou-Alfa et al

4. RAS Endothelial cell or Pericyte Angiogenesis: PDGF-  VEGF VEGFR-2 PDGFR-  Paracrine stimulation Mitochondria Apoptosis Tumor cell PDGF VEGF EGF/HGF Proliferation Survival Mitochondria EGF/HGF HIF-2 Autocrine loop Apoptosis ERK RAS MEK RAF Nucleus ERK MEK Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis Wilhelm S et al. Cancer Res. 2004;64:7099-7109. RAF Differentiation Proliferation Migration Tubule formation Sorafenib Nucleus

5. Management of Hepatocellular Carcinoma: Sorafenib phase II data Child’s A + B, untreated 400 mg bid continuous N = 137 PR = 2.2% MR = 5.8% TTP = 4.2 months OS = 9.2 months Abou-Alfa, et al; JCO, 2006

6. Abou-Alfa et al, JCO, 2007

7. 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

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

9. Patient characteristics Characteristics Sorafenib (n=299) Placebo (n=303) Age (yr, median)6566 Male/Female (%)87/13 Region (Europe/N. America/other; %)88/9/387/10/3 Etiology Viral hepatitis (HCV/HBV) Alcohol/other 29/19 26/26 27/18 26/29 Child-Pugh (A/B; %)95/598/2 Prior therapies: Surgical resection Loco-regional therapies 19% 39% 21% 41%

10. Sorafenib Median: 46.3 weeks (95% CI: 40.9, 57.9) Survival Probability Weeks Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88) P=0.00058* Placebo Median: 34.4 weeks (95% CI: 29.4, 39.4) 1.00 0 0.75 0.50 0.25 08081624324048566472 *O’Brien-Fleming threshold for statistical significance was P=0.0077. 02742412051611086738120 Patients at risk Sorafenib: 027622417912678472572 Placebo: 299 303 Overall survival (Intention-to-treat)

11. Phase III SHARP Trial Response assessment FSHI8-TSP: No significant differences between treatment groups (P=0.77). 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 disease54(71%)73(24%) Progression-free rate at 4 mo62%42% Duration of treatment (median, weeks) 2319

12. Child’s Pugh Score of Liver Cirrhosis Parameter Points 123 Albumin (g/dL)> 3.52.8 - 3.5< 2.8 Bilirubin (mg/dL)< 22 - 3> 3 Ascites Absent Slight Moderate EncephalopathyNoneI - IIIII - IV PT (INC)< 1. 71.8 - 2.3> 2.3 ScoreABC Points5 - 67 - 910 - 15 Pugh, RNH, et al. British Journal of Surgery. 60 (8): 646 -649, 1973

14. Luigi Bolondi, MD “Alma Mater Studiorum” University of Bologna, Bologna, Italy W Caspary, J Bennouna, B Thomson, W Van Steenbergen, F Degos, M Shan, D Voliotis, M Moscovici, J Bruix, for the SHARP Investigators Study Group Clinical Benefit of Sorafenib in Hepatitis C Patients With Hepatocellular Carcinoma (HCC): Subgroup Analysis of the Sorafenib HCC Assessment Randomized Protocol (SHARP) Trial

15. Other Alcohol Hepatitis B Hepatitis C 50%-70% 70% 20% 10%-20% ≤10% 020406080 Cases (%) Risk Factors for HCC Worldwide *Excluding Japan. 1. Llovet JM et al. Lancet. 2003;362:1907-1917. 2. Llovet J et al. J Clin Oncol. 2007;25(Suppl 18):LBA1. % of Patients With Risk Factor in SHARP 2 Sorafenib (n=299) Placebo (n=303) 2927 19 26 910 Asia/Africa* Europe/N. America Japan All

16. SHARP: OS in Patients With HCV Sorafenib Median: 14.0 mo 95% CI: 9.9-N/E* HR (95% CI): 0.58 (0.37-0.91) Placebo Median: 7.9 mo 95% CI: 5.4-9.8 Months From Randomization 4681416 Probability of Survival 0 0.25 0.50 0.75 1.00 0 *N/E = not estimable. 2 1012

17. SHARP: Summary of Efficacy Measures by HCV Status HCV-positiveOverall population 1 Sorafenib (n=93) Placebo (n=85) Sorafenib (n=299) Placebo (n=303) DCR (%)44.130.643.531.6 Med. TTP, mo7.62.85.52.8 HR (95% CI)0.44 (0.25-0.76) 0.58 (0.44-0.74) Med. OS, mo14.07.910.77.9 HR (95% CI) 0.58 (0.37-0.91) 0.69 (0.55-0.88) 1. Llovet J et al. J Clin Oncol. 2007;25(Suppl 18):LBA1.

18. Final results of phase II, randomized, double-blind study of sorafenib plus doxorubicin and placebo plus doxorubicin in patients with advanced hepatocellular carcinoma Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T, Mori A, Leberre M-A, Voliotis D, and Saltz LB Memorial Sloan-Kettering Cancer Center, New York, USA, The University of Birmingham, Birmingham, UK, Princess Margaret Hospital, Toronto, Canada, Krasnodar City Oncology Center, Krasnodar, Russia, Unidad Oncologica de Neuquen, Neuquen, Argentina, Hong Kong Sanatorium & Hospital, Hong Kong, Bayer Healthcare Pharma, Puteaux, France, Bayer HealthCare, France, Bayer HealthCare, West Haven, USA

19. Study Design Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent Eligibility  Child-Pugh A  ECOG PS: 0, 1, 2 (1:1) Randomization (N~96) Period 1Period 2 Continue until withdrawal, PD,or death 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Sorafenib 400 mg po bid 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Placebo 2 tablets po bid Sorafenib 400 mg po bid

20. Results DXR/sorafenib (n=47) DXR/placebo (n=49) TTP (months)8.64.8 OS (months)13.86.5 PFS (months)6.92.8 Response (CR+PR) n(%) 2 (4)1 (2) Response (SD)36 (77)27 (55) Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 51 events, PFS: 70 events )

21. Sorafenib in HCC: Child’s Pugh A Subset analysis suggests comparable outcome and toxicity compared to entire cohort HCV patients under-represented on this study given the distribution of risk factors worldwide These are still high performance HCV / HCC patients The sum of the data reinforces the efficacy of sorafenib as a single agent in Child’s-Pugh A patients

22. Sorafenib / doxorubicin: HCC Child’s A Randomized phase II so direct comparison between arms not planned: “exploratory” No stratification; under-powered LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity

23. Sorafenib / doxorubicin: HCC Child’s A Randomized phase II so direct comparison between arms not planned: “exploratory” No stratification; under-powered LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity Are these results enough to sway the disbelievers?

24. Sorafenib / doxorubiNIB: HCC Child’s A Randomized phase II so direct comparison between arms not planned: “exploratory” No stratification; under-powered LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity Are these results enough to sway the disbelievers?

25. Sorafenib / doxoruZIMAB: HCC Child’s A Randomized phase II so direct comparison between arms not planned: “exploratory” No stratification; under-powered LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity Are these results enough to sway the disbelievers?

26. Sorafenib in HCC: Next questions How does sorafenib work? Do these findings apply to Child’s-B or C ? What is the proper dose of sorafenib in such pts? Can it be combined with other agents? Might it be active in the “adjuvant” setting? Could it be used in conjunction with TACE?

27. Sorafenib in HCC: Next studies Adjuvant after RFA / resection Sorafenib +/- erlotinib Bayer / Onyx Sorafenib +/- doxorubicin TACE +/- sorafenib Intergroup Other sorafenib combinations

28. Sorafenib in HCC: Take home message Phase II data in HCC is difficult to interpret Studies in HCC need to first be done in the most fit patients, then generalized if possible These advances, while landmark, are modest and much work needs to be done

29. Sorafenib in HCC: Take home message Phase II data in HCC is difficult to interpret Studies in HCC need to first be done in the most fit patients, then generalized if possible These advances, while landmark, are modest and much work needs to be done Cost = $5416 / month