1. Jorge A. Marrero, MD, MS Keith S. Henley, MD, Professor of Gastroenterology Director, Multidisciplinary Liver Tumor Clinic University of Michigan Health System Ann Arbor, Michigan Current Treatment of Advanced HCC This program is supported by an educational grant from

2. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Program Faculty Alan P. Venook, MD Professor of Clinical Medicine Department of Hematology and Oncology Division of Medical Oncology University of California, San Francisco San Francisco, California Jorge A. Marrero, MD, MS Keith S. Henley, MD, Professor of Gastroenterology Director, Multidisciplinary Liver Tumor Clinic University of Michigan Health System Ann Arbor, Michigan Jorge A. Marrero, MD, MS, has disclosed that he has received consulting fees from Abbott and Kowa and contracted research from Bayer/Onyx, Bristol-Myers Squibb, Eli Lilly and Company, and Pfizer. Alan P. Venook, MD, has disclosed that he has received contracted research from Genentech, Genomic Health, GlaxoSmithKline, and Novartis. Disclosures

4. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Overview  Treatment selection –Risk factors –Diagnosis –Tumor staging  Treatment of nonresectable HCC

5. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Malignant Transformation: Multistep Potential Targets Oxidative stress and inflammation Viral oncogenes Carcinogens Growth factorsTelomere shortening Cancer stem cells Loss of cell cycle checkpoints AntiapoptosisAngiogenesis Normal liver Liver cirrhosis Hepatitis C Hepatitis B Ethanol NASH Epigenetic alterations Genetic alterations HCC [2] Dysplastic nodules [1] 1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.

6. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Vascularity of HCC

7. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC VariableOdds Ratio (95% CI) All patients (N = 124)  AFP > 20 ng/mL11.7 (2.3-30.7)  Washout61 (3.8-7.3) Tumor < 2 cm only (n = 35)  Washout6.3 (1.8-13) Importance of Contrast Washout of an Arterially Enhancing Mass Marrero JA, et al. Liver Transpl. 2005;11:281-289.

8. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Contrast Washout in HCC Arterial PhasePortal Venous Phase

9. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Atypical Hepatocellular Carcinoma  85% of hepatocellular carcinomas > 2 cm have “washout”  Some lesions are atypical  Biopsy is important for these lesions ArtDelArtDel Bolondi L, et al. Hepatology. 2002;42:27-34.

10. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC P <.0001 Survival Probability (%) Mos 0 20 40 60 80 100 01224364860 BCLC B BCLC C N = 112 Llovet JM, et al. Hepatology. 1999;29:62-67. Survival Rates in Patients with Intermediate- and Advanced-Stage HCC

11. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Beaugrand M, et al. J Hepatol. 2003;42;17A. Abstract 37. Seocalcitol vs Placebo in Unresectable HCC: OS 06121824303642 Mos Since Treatment Start 1.00 0.75 0.50 0.25 0 Probability of Survival P =.76 Intermediate Stage (BCLC B; n = 370) Stage 0 Median survival:Placebo 15.8 mos Seocalcitol 15.1 mos Group 0 Group 1 06121824303642 Mos Since Treatment Start 1.00 0.75 0.50 0.25 0 Probability of Survival P =.37 Advanced Stage (BCLC C; n = 376) Stage 1 Median survival:Placebo 5.7 mos Seocalcitol 5.6 mos Group 0 Group 1

12. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SHARP: Subgroup Analyses SubgroupNDefTTP, MosOS, MosAdverse Events Macroscopic vascular invasion/extrahepatic spread [1] 421+4.1 vs 2.78.9 vs 6.7Grade III/IV: diarrhea 5% vs 16%, hand-foot syndrome 7% vs 10%, fatigue 5% vs 1% 181-9.6 vs 4.314.5 vs 10.2 ECOG performance score [2] 32505.5 vs 2.913.3 vs 8.8Grade III/IV: diarrhea 9% vs 8%, hand-foot syndrome 9% vs 7%, fatigue 3% vs 5%, rash/desquamation 2% vs 0% 2271-25.3 vs 2.88.9 vs 5.6 Alcohol-related etiology [3] 79+ S5.5 vs 3.910.3 vs 8.0All grades: diarrhea 47.4% vs 10%, fatigue 20.5% vs 12.5%, hand-foot syndrome 20.5% vs 6.3% 80+ P Hepatitis C etiology [4] 93+ S7.6 vs 2.814.0 vs 7.9Grade III/IV: diarrhea 11% vs 3%, hand-foot syndrome 13% vs 0%, fatigue 7% vs 8 %, hyperbilirubinemia 10% vs 2%, ascites 7% vs 9% 85+ P 1. Sherman M, et al. ASCO 2008. Abstract 4584. 2. Raoul J, et al. ASCO 2008. Abstract 4587. 3. Craxi A, et al. ASCO 2008. Abstract 15591. 4. Bolondi L, et al. ASCO GI 2008. Abstract 129.

13. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Staging Systems in HCC Marrero JA, et al. Hepatology. 2005;41:707-716. Staging System Hepatic FunctionAlpha- fetoprotein Performance Score Tumor Staging OkudaAscites, albumin, and bilirubin No Tumor > or < 50% of cross- sectional area of liver TNMNo Number of nodules, tumor size, presence of portal vein thrombosis, and presence of metastasis CLIPCTP< 400 or ≥ 400 ng/mL NoNumber of nodules, tumor > or < 50% area of liver, and portal vein thrombosis BCLCCTPNoYesTumor size, number of nodules, and portal vein thrombosis CUPIBilirubin, ascites, alkaline phosphatase < 500 or ≥ 500 ng/mL Presence of symptoms TNM JISCTPNo TNM GRETCHBilirubin, alkaline, phosphatase < 35 or ≥ 35 µg/L YesPortal vein thrombosis

14. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Liver transplantation (CLT/LDLT) PEI/RFA Systemic treatment Curative treatments 50% to 75% at 5 yrs Randomized controlled trials 40% to 50% at 3 yrs vs 10% at 3 yrs Chemoembolism Single Increased Associated diseases NormalNoYes Terminal stage (D) Symptomatic treatment Stage A-C Okuda 1-2, PST 0-2, Child-Pugh A-B Portal pressure/bilirubin 3 nodules ≤ 3 cm Intermediate stage (B) Multinodular, PST 0 Okuda 3, PST > 2, Child-Pugh C Stage D Very early stage (0) Single < 2 cm Carcinoma in situ Early stage (A) Single or 3 nodules < 3 cm, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1-2 PST 0, Child-Pugh A Stage 0 Resection Barcelona Clinic Liver Cancer Staging Classification Llovet JM et al. Lancet. 2003;362:1907-1917.

15. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Chemoembolization Image courtesy of www.hopkinscoloncancercenter.org.

16. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Transarterial Chemoembolization in Hepatocellular Carcinoma: Survival Lin, Gastroenterology 1988 63 GETCH, N Engl J Med 1995159 Bruix, Hepatology 1998239 Pelletier, J Hepatology 1998312 Lo, Hepatology 2002391 Llovet, Lancet 2002501 Overall503 Llovet JM, et al. Hepatology. 2003;37:429-442. Favors TACEFavors Control

17. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Patients (%) Child-Pugh BECOG 1BilobarRecurrent Disease Complete responseObjective responseDisease control 4 (25%) 7 (44%) 10 (63%) 3 (16%) 4 (21%) 6 (32%) 7 (37%) 12 (63%) 4 (14%) 8 (29%) 9 (32%) 7 (17%) 20 (49%) 24 (59%) 6 (13%) 18 (40%) 22 (49%) 3 (27%) 6 (55%) 8 (73%) 2 (15%) 4 (31%) 7 (54%) Lammer J, et al. Cardiovasc Intervent Radiol. 2010;33:41-52. PRECISION V: Conventional TACE vs DEB TACE 0 10 20 30 40 50 60 70 DC beadcTACEDC beadcTACEDC beadcTACEDC beadcTACE

18. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Phase III Study: Sorafenib vs Placebo After TACE in Unresectable Asian Patients Primary endpoint: TTP (time to recurrence with CR, TTP if no CR) Secondary endpoint: OS Patients with unresectable HCC, Child-Pugh A cirrhosis, and tumor shrinkage and/or necrosis ≥ 25% in response to TACE (N = 458) Sorafenib 400 mg BID (n = 229) Placebo (n = 229) Kudo M, et al. Eur J Cancer. 2011;47:2117-2127. Stratified by response to TACE (CR vs non-CR), ECOG PS (1 vs 2), and TACE courses (1 vs 2)

19. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Sorafenib vs Placebo After TACE in Unresectable Asian Patients: Results Kudo M, et al. Eur J Cancer. 2011;47:2117-2127. Investigator-assessed TTP: 7.2 mos with sorafenib vs 5.3 mos with placebo (HR: 0.79; P =.049) TTP (Central Review)OS (Investigator Assessment) 1.00 0.75 0.50 0.25 0 Progression-Free Probability 036612182430 Mos From Randomization HR (S/P): 0.87 (95% CI: 0.70-1.09; P =.252, 2 sided) Sorafenib (n = 229) Median: 5.4 mos (95% CI: 3.8-7.2) Censored Placebo (n = 229) Median: 3.7 mos (95% CI: 3.5-4.0) Censored 1.00 0.75 0.50 0.25 0 Progression-Free Probability 036612182430 Mos From Randomization HR (S/P): 1.06 (95% CI: 0.69-1.64; P =.790, 2 sided) Sorafenib (n = 229) Median: 29.7 mos (95% CI: 28.6-NE) Censored Placebo (n = 229) Median: NE (95% CI: NE-NE) Censored

20. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SPACE: Study Schema  Primary endpoint: TTP (central review)  Secondary endpoints: OS, time to VI/EHS, time to untreatable progression, safety Patients with unresectable HCC, Child-Pugh A cirrhosis, no ascites or encephalopathy, ECOG PS 0 (N = 307) Sorafenib 400 mg BID TACE* (n = 154) Placebo TACE* (n = 153) Lencioni R, et al. ASCO GI 2012. Abstract LBA154. Progression *First TACE with DEBDOX performed 3-7 days after first day of treatment with sorafenib or placebo. Subsequent TACE with DEBDOX performed on Day 1 (± 4 days) of cycles 3, 7, and 13, and every 6 cycles thereafter. Patients allowed optional TACE with DEBDOX sessions between cycles 7 and 13 and cycles 13 and 19, if deemed necessary by the investigator.

21. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SPACE: TTP by Central Review (Primary Endpoint) HR: 0.797 (95% Cl: 0.588-1.08; P =.072) Sorafenib Median: 169 days (95% Cl: 166-219) Placebo Median: 166 days (95% Cl: 113-168) Lencioni R, et al. ASCO GI 2012. Abstract LBA154. 1.00 0.75 0.50 0.25 0 Progression-Free Probability 0100200300400500600700 Patients at Risk, n Sorafenib Placebo 154 153 0101 86 9133 16 125 2424 Days

22. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SPACE: Time to Vascular Invasion/ Extrahepatic Spread HR: 0.621 (95% Cl: 0.321-1.200; P =.076) Sorafenib Median: NR Placebo Median: NR 1.00 0.75 0.50 0.25 0 VI/EHS-Free Probability 0100200300400500600700 Patients at Risk, n Sorafenib Placebo 154 153 3232 102 116 60 74 40 47 20 22 9 14 Lencioni R, et al. ASCO GI 2012. Abstract LBA154. Days

23. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SPACE: Overall Survival HR: 0.898 (95% Cl: 0.606-1.33; P =.295) Sorafenib Median: NR (95% CI to 554 days, NR) Placebo Median: NR (95% CI to 562 days, NR) 1.00 0.75 0.50 0.25 0 Survival Probability 0100200300400500600700 Patients at Risk, n Sorafenib Placebo 154 153 23 143 142 126 127 111 109 74 7344 54540 800 Lencioni R, et al. ASCO GI 2012. Abstract LBA154. Days

24. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Molecular Signaling Pathways in HCC Wilhelm S, et al. Cancer Res. 2004;64:7099-7109. Autocrine loop Tumor Blood Vessels Tumor Cell Growth and survival factors (eg, VEGF, PDGF) Sorafenib PDGF VEGF EGF/HGF Proliferation Survival Mitochondria EGF/HGF HIF-2 Nucleus Apoptosis ERK RAS MEK RAF

25. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Phase III SHARP Study: Sorafenib vs Placebo in Advanced HCC Primary endpoints: OS, time to symptomatic progression Secondary endpoint: TTP (independent review) Llovet JM, et al. N Engl J Med. 2008;359:378-390. Stratified by macroscopic vascular invasion and/or extrahepatic spread; ECOG PS; geographical region Patients with advanced hepatocellular carcinoma, ECOG PS ≤ 2, no previous systemic treatment (N = 602) Sorafenib 400 mg PO BID, continuous dosing (n = 299) Placebo 2 tablets PO BID, continuous dosing (n = 303)

26. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SHARP: Baseline Patient Characteristics CharacteristicSorafenib (n = 299) Placebo (n = 303) Median age, yrs6566 Male, %87 Etiology, %  HBV1918  HCV2927  Alcohol only26  Other910 Previous therapies, %  Surgical resection1921  Locoregional therapies2930 Llovet JM, et al. N Engl J Med. 2008;359:378-390.

27. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Sorafenib in Advanced HCC (SHARP): Survival Survival Probability Mos Since Randomization 1.00 0 0.75 0.50 0.25 Sorafenib median OS: 46.3 wks (10.7 mos) (95% CI: 40.9-57.9) Placebo median OS: 34.4 wks (7.9 mos) (95% CI: 29.4-39.4) HR (S/P): 0.69 (95% CI: 0.55-0.87; P <.001) Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390. 01234568910111213141516717

28. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Sorafenib in Advanced HCC (SHARP): TTP Sorafenib (n = 299) Placebo (n = 303) Number failed, n (%)107 (36)156 (52) Number censored, n (%)192 (64)147 (49) Median TTP, mo (95% CI)5.52.8 HR (95% CI) S/P0.58 (0.45-0.74) P value<.001 Progression-Free Probability 546121824303642480 Wks 1.00 0 0.75 0.50 0.25 Placebo Sorafenib Llovet JM, et al. ASCO 2007. Abstract LBA1. Adapted from Llovet JM, et al. N Engl J Med. 2008;359:378-390.

29. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Sorafenib vs Placebo in Advanced HCC (SHARP): Response Time to symptom progression (FSHI8-TSP scoring): no significant differences between treatment groups (P =.77) *RECIST criteria, independent review. Result Sorafenib (n = 299) Placebo (n = 303) Overall response,* n (%)  CR 0 (0)  PR 7 (2.3)2 (0.7) SD, n (%) 211 (71)204 (67) PD, n (%)54 (18)73 (24) PFS rate at Month 4, %6242 Median treatment duration, wks2117 Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.

30. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC SHARP: Adverse Events SAEs, %Sorafenib (n = 299)Placebo (n = 302) Overall SAEs5254 Drug-related SAEs139 Drug-Related AEs, %Grade Any3/4Any3/4 Diarrhea398/0112/0 Hand-foot skin reaction218/03< 1/0 Anorexia14< 1/031/0 Alopecia140/02 Nausea11< 1/081/0 Weight loss92/010/0 Pain (abdomen)82/031/0 Bleeding71/041/< 1 Vomiting51/03 Liver dysfunction< 1< 1/000/0 Llovet JM, et al. N Engl J Med. 2008;359:378-390.

31. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Conclusions  HCC occurs in cirrhotic patients and complicates diagnosis and treatment  The Barcelona Clinic Liver Cancer staging system accounts for key prognostic factors: hepatic function, performance score, and tumor burden  Chemoembolization is the best option in nonresectable patients without vascular involvement  Sorafenib is the best option for advanced tumors  Novel therapies are needed

32. clinicaloptions.com/oncology Current Therapy and Novel Agents clinicaloptions.com/oncology Current Treatment of Advanced HCC Go Online for More CCO Coverage of Oncology! Capsule Summaries of key studies Expert Analysis panel discussions exploring the clinical implications Downloadable Slidesets highlighting the most important findings in specific tumor types clinicaloptions.com/oncology