1 / 27

Sorafenib and HCC: Is It All About VEGF?

Sorafenib and HCC: Is It All About VEGF?. Bert H O'Neil UNC Lineberger Comprehensive Cancer Center Chapel Hill, NC. Sorafenib Phase II: Child-Pugh B Cirrhosis. OS=overall survival; SD=stable disease; TTP=time to tumor progression.

jacoba
Télécharger la présentation

Sorafenib and HCC: Is It All About VEGF?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related