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Sorafenib and HCC: Is It All About VEGF?
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Sorafenib and HCC: Is It All About VEGF?

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  1. Sorafenib and HCC: Is It All About VEGF? Bert H O'NeilUNC Lineberger Comprehensive Cancer CenterChapel Hill, NC

  2. Sorafenib Phase II: Child-Pugh B Cirrhosis 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) 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* * 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. Duration of Sorafenib Therapy by Child­Pugh Status* 46% 30% * Data at study entry. Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

  8. Preliminary Time-to-Progression*by Child-Pugh Status† at Study Entry Child-Pugh A (<7) (n=984), median (95% CI) 129 (119, 146) days 4.2 months 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 TTP distribution function Time since start of treatment (days) * 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.

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

  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 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) Sunitinib Median 7.9 months (95% CI: 7.4-9.2) 1.00 Sorafenib Median 10.2 months (95% CI: 8.9-11.4) 0.75 HR 1.30 (95% CI: 1.13-1.50) P=.0010 0.50 OS probability (%) 0.25 0.0 0 5 10 15 20 25 30 35 40 Time (months) 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) * 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* * 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 Sunitinib Sorafenib Inhibited by Sunitinib Inhibited by both Inhibited by Sorafenib 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.

  20. No Activity With MEK Inhibitor Selumetinib (AZ6244) in HCC Posttreatment Posttreatment Posttreatment Posttreatment Posttreatment Baseline Baseline Baseline Baseline Baseline pERK1/2 ERK1/2 Zero radiographic responsesTTP ≈8 weeks 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.

  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) ITT Population Sunitinib (n=113) Median 9.2 months (95% CI: 7.0-12.0) Sorafenib (n=119) Median 17.6 months (95% CI: 11.4-) HR 1.52 (95% CI: 1.09-2.13) P=.0165 OS probability (%) Time (months) P-values based on stratified log-rank test. Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

  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. 90,000 80,000 70,000 60,000 50,000 Activity 40,000 30,000 20,000 10,000 0 6-cont 5 Msorafenib 7.5 Msorafenib 10 Msorafenib 15 Msorafenib 20 Msorafenib sorafenib untreated 12.5 M 7.5 M 15 M 20 M 10 M 5 M H2O HCV actin Before therapy During therapy 1.00E-07 1.00E-06 1.00E-05 Genomes/mL 1.00E-04 1.00E-03 1.00E-02 Patient 1 Patient 2 Patient 3 HCV replication inhibition 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.

  25. Do HCV-Associated miRNAs Sensitize Cells to Sorafenib? 140 Hep-SWX cells Control pre-miR 120 Hep-394 cells 120 Pre-miR-193b 100 100 80 80 Cell viability (%) Cell viability (%) 60 60 40 40 20 20 0 0 0.001 0.1 10 1000 0.001 0.1 10 Sorafenib (M) Sorafenib (M) Cells transfected with HCV genome Cells transfected with miRNAinduced by HCV 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.

  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.