1. Sorafenib and HCC: Is It All About VEGF? Bert H O'Neil UNC Lineberger Comprehensive Cancer Center Chapel Hill, NC

2. Sorafenib Phase II: Child-Pugh B Cirrhosis Therapy Child-Pugh A n=98 Child-Pugh B n=38 Length of therapy (weeks)2513 Dose reduction31%21% Outcomes Child-Pugh A n=98 Child-Pugh B n=38 SD (≥4 months)49%26% TTP (median)21 weeks13 weeks OS41 weeks14 weeks OS=overall survival; SD=stable disease; TTP=time to tumor progression. Abou-Alfa GK et al. J Clin Oncol. 2008;26(15S):Abstract 4518. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

3. Adverse Events (Note Half Exposure for C­P B Patients) Events (%) Child-Pugh A n=98 Child-Pugh B n=38 All adverse events97 Serious adverse events5268 Fatigue4137 Diarrhea5947 Hand-foot syndrome3013 Increased bilirubin1840 Encephalopathy211 Worsening ascites1118 C-P=Child-Pugh. Abou-Alfa GK et al. J Clin Oncol. 2008;26(15S):Abstract 4518. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

4. GIDEON and C-P B GIDEON is a registry that tracks the ‘real-world’ use of sorafenib in about 3200 patients in 32 countries without a prespecified hypothesis The SHARP study was comprised almost exclusively of patients with well-compensated C-P A) cirrhosis GIDEON can provide us with important information on safety and single-arm efficacy in the C-P B population GIDEON=Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib; SHARP=Study of Heart and Renal Protection. Llovet J et al. N Engl J Med. 2008;359:378-390. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

5. GIDEON and C-P B (cont’d) Similar numbers started with standard dose sorafenib Mean and median dose was similar Surprisingly, dose interruptions and modifications were similar Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

6. Overview of Treatment-Emergent Safety Data by Child-Pugh Status* % of n Total † (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) AEs (all Grades)83828986 Drug-related AEs (all Grades)64676346 AEs (Grade 3/4)30293134 Drug-related AEs (Grade 3/4)23242223 SAEs ‡ 37295663 Drug-related SAEs ‡ 98156 AEs resulting in permanent discontinuation of sorafenib § 28243851 Deaths ║ 22163437 *Data at study entry; † Child-Pugh status missing or not evaluable for 56 patients; ‡ An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death, life-threatening, hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, medically important event; § Any AE; ║ Treatment-emergent deaths occurring up to 30 days after last sorafenib dose. AEs=adverse events; SAEs=serious adverse events. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

7. Total (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) ≤4 weeks, %17132346 >4-8 weeks, %181723 >8-20 weeks, %35382823 >20-28 weeks, %121390 >28 weeks, %1618146 Median treatment duration, weeks 121494 Duration of Sorafenib Therapy by Child­Pugh Status* *Data at study entry. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 30% 46%

8. Preliminary Time-to-Progression * by Child-Pugh Status † at Study Entry * TTP was documented radiological disease progression; RECIST v. 1.0 used for tumor evaluation; † 207 patients not evaluable. RECIST=Response Evaluation Criteria in Solid Tumors. Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Child-Pugh A (<7) (n=984), median (95% CI) 129 (119, 146) days 4.2 months TTP distribution function Child-Pugh B (7-9) (n=376), median (95% CI) 109 (93, 140) days 3.6 months Child-Pugh C (>9) (n=36), median (95% CI) 64 (28, 110) days 2.1 months Time since start of treatment (days)

9. Preliminary Overall Survival by Child-Pugh Status * at Study Entry * 207 patients not evaluable. CI=confidence interval. Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Child-Pugh A (<7) (n=984), median (95% CI) 312 (284, 341) days 10.3 months Survival distribution function Time since start of treatment (days) Child-Pugh B (7-9) (n=376), median (95% CI) 147 (126, 189) days 4.8 months Child-Pugh C (>9) (n=36), median (95% CI) 62 (46, 94) days 2.0 months

10. What Does GIDEON Add? GIDEON suggests that safety is similar between C­P A and C-P B patients However, duration of therapy for the C-P B population was exceedingly short—8.5 weeks This suggests that equivalent numbers of adverse events occur in a shorter period of time The low number of dose reductions in the C­P B population is also interesting, but is also affected by the short treatment duration Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

11. What Does GIDEON Add? (cont’d) Does GIDEON suggest we should be starting sorafenib at full dose in future studies in the C­P B population? YES Do GIDEON’s results support the routine use of sorafenib in the C­P B population? NO—this use should be considered investigational and standard of care remains best supportive care Authors’ conclusions appropriately conservative in this regard Reminds us that testing drugs in C­P A population is best Adapted from O'Neil BH et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

12. Sunitinib vs Sorafenib Sunitinib has good efficacy in RCC compared to sorafenib and produced Phase II results in HCC comparable to those seen with sorafenib Different kinase inhibition profiles might suggest differential activity between these agents in HCC However, no strong a priori hypothesis regarding non–VEGF- related targets HCC=hepatocellular carcinoma; RCC=renal cell carcinoma; VEGF=vascular endothelial growth factor. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

13. Cross-Trial Characteristics SHARP n=299 Asian Study n=150 Sun vs Sor N=544 Median age65 yrs52 yrs59 yrs Male87%85%84% Viral hepatitis B/C19/29%71/11%53/22% Child-Pugh (A/B)95/5%97/3%100/0 ECOG performance status 0/154/38%25/70%53/47 Vascular invasion/ Extrahepatic spread 36/53%36/69%31/76% Surgical resection Loco-regional therapy 19% 48% NR100%? ECOG=Eastern Cooperative Oncology Group; NR=no response. Llovet J et al. N Engl J Med. 2008;359:378-390; Cheng AL et al. Lancet Oncology. 2009;10:25-34. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

14. OS—Primary Endpoint (ITT Population) Sunitinib530354208112418000 Sorafenib5443882451396112100 Time (months) OS probability (%) 051015 0.0 2025303540 Sunitinib Median 7.9 months (95% CI: 7.4-9.2) Sorafenib Median 10.2 months (95% CI: 8.9-11.4) 1.00 0.75 0.50 0.25 HR 1.30 (95% CI: 1.13-1.50) P=.0010 Patients at risk P-value based on stratified log-rank test. CI=confidence interval; HR=hazard ratio. Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

15. What Can We Learn From This Negative Trial (Other Than the Obvious)? Was toxicity the main difference-maker? Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

16. Overview of Treatment-Emergent AEs (All Causes; As-Treated Population) Sunitinib (n=526) Sorafenib (n=542) Any AE100% Serious AEs45%37% Grade* 3 or 4 AEs82%74% Grade* 5 AEs19%17% Discontinued due to AEs13% Temporarily discontinued due to AEs77%59% Dose reduced due to AEs30%35% *National Cancer Institute—Common Terminology Criteria for AEs (NCI-CTCAE) v3.0. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

17. Deaths on Study* Event Sunitinib (n=526) Sorafenib (n=542) Deaths (all causes; n, %)92 (17%)83 (15%) Cause (% of total deaths: SU n=92; SO n=83) † Disease progression76%86% Toxicity18%2% Dehydration ± organ failure3%0 CNS hemorrhage3%0 Esophageal varices/GI hemorrhage † 3%1% Other/unknown cause7%13% Pneumonia2%1% Septic shock/sepsis1%2% Unknown reason02% *Deaths during the study or within 28 days after the last dose of study medication. Participants may have more than one cause of death; † Includes deaths attributed to tumor hemorrhage. CNS=central nervous system; GI=gastrointestinal; SU=sunitinib; SO=sorafenib. Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

18. What Can We Learn From This Negative Trial (Other Than the Obvious)? Are there potential biologic explanations for differential results? VEGFRs? RAFs Other? Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

19. Kinase Profiles PDGFRB0.075MLCK23KIT0.1 KIT0.37TNIK25DDRI1.5 FLT30.47MERTK26XAK6.3 PDGFRA0.79CLK429DDR 26.6 DRAK 11RIOK135FLT 313 VEGFR21.5LKB138PET13 VEGFR1 (FLT-1)1.8PIP5K2B39CFS 1R28 BIKE5.5MAP4K541VEGFR1 (FLT-1)31 PHKG 15.5ARK 548B37 PHKG 25.9JAK 149FLK 846 AXL9MYLK249VEGFR259 AAK 111TYRO349PDGFRA62 RET12FLT450TIE 168 CSNK 1E13MST 256FLT 495 ITK13SLK56 BRAF V600E260 CSNK 1D15MST 363 SgK 08515TTK63 MAP4K116BLK65 RAF1 (c-RAF)230 PAK 316CAMK2A80 STK 3317CSNK 2A181 AMPK  1 19PTK 2B82 LOK19 AMPK  2 89 MST 119PLK100 CLK 220TRKA100 GAK20 CLK 122 DAPK322 Karaman MW et al. Nat Biotechnol. 2008;26(1):127-132. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. SunitinibSorafenib Inhibited by Sunitinib Inhibited by both Inhibited by Sorafenib

20. No Activity With MEK Inhibitor Selumetinib (AZ6244) in HCC O’Neil B et al. J Clin Oncol. 2011; in press. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. pERK1/2 ERK1/2 Baseline Posttreatment Baseline Posttreatment Baseline Posttreatment Baseline Posttreatment Baseline Posttreatment Zero radiographic responses TTP ≈8 weeks

21. Sorafenib and HCV-Related HCC Subgroup analysis of HCV-infected patients in SHARP Placebo 7.9 mo Sorafenib group 14 mo HCV=hepatitis C virus. Bolondi L et al. ASCO GI Annual Meeting; January 25-27, 2008; Orlando, FL. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

22. OS in Patients With HCV Infection (Exploratory Analysis) P-values based on stratified log-rank test. Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. OS probability (%) Time (months) Sunitinib ITT Sorafenib ITT Sunitinib Asia Sorafenib Asia Sunitinib Ex-Asia Sorafenib ex-Asia Median OS, months9.217.69.712.68.618.3 HR (95% CI)1.52 (1.09-2.13)1.40 (0.92-2.14)1.76 (0.99-3.10) P-value (1-sided).0165.0721.0544 Sunitinib (n=113) Median 9.2 months (95% CI: 7.0-12.0) Sorafenib (n=119) Median 17.6 months (95% CI: 11.4-) ITT Population HR 1.52 (95% CI: 1.09-2.13) P=.0165

23. HCV NS5A and HCC Nonstructural HCV protein that interacts with a large number of cellular proteins, including oncogenes Recent evidence suggests c-RAF is part of the HCV replication complex Sorafenib produced c-RAF dependent decrease in HCV replication This effect was not replicated with 2 different MEK inhibitors! Himmelsbach K et al. Gut. 2009;58:1644-1653. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

24. Himmelsbach K et al. Gut. 2009;58:1644-1653. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Patient 1Patient 2Patient 3 Before therapy During therapy 1.00E-02 1.00E-03 1.00E-04 1.00E-05 1.00E-06 1.00E-07 Genomes/mL 6-cont 0 20,000 40,000 60,000 10,000 30,000 50,000 70,000 80,000 90,000 5  M sorafenib 7.5  M sorafenib 10  M sorafenib 15  M sorafenib 20  M sorafenib untreated 5  M 7.5  M 10  M 12.5  M 15  M20  M H2OH2O HCV actin sorafenib Activity HCV replication inhibition

25. Do HCV-Associated miRNAs Sensitize Cells to Sorafenib? miRNA=micro RNA. Braconi C et al. Clin Cancer Res. 2010;16(3)957-966. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Cells transfected with HCV genomeCells transfected with miRNA induced by HCV 0.0010.110 0 20 40 60 80 100 120 140 0.0010.1101000 Sorafenib (  M) 0 20 40 60 80 100 120 Hep-SWX cells Hep-394 cells Control pre-miR Pre-miR-193b Cell viability (%) Sorafenib (  M)

26. Summary Sorafenib can be used with relative safety in the C­P B HCC population But OS appears to be short Sorafenib was superior to sunitinib for HCC The superiority of sorafenib over sunitinib in HCV-infected patients raises interesting questions about non–VEGFR-related activities of sorafenib Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

27. Do We Need More VEGF Inhibitors for HCC? Experience in RCC might suggest yes A better-tolerated VEGFR agent would be welcome Sunitinib does not fill this role Others may, including bevacizumab Studies of brivanib and linifanib vs sorafenib should report in the near future Caution that Phase II data for all of these agents have looked similar, risk of Phase III trial failure may be high Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.