MasterClass & Tumor Board Composing Personalized HCC Treatment Strategies

1. MasterClass & Tumor Board Composing Personalized HCC Treatment Strategies Insights on Harmonizing Patient Care With a Multidisciplinary Ensemble

2. Welcome to “Composing Personalized HCC Treatment Strategies: Insights on Harmonizing Patient Care With a Multidisciplinary Ensemble” • Today’s panelists: GhassanAbou-Alfa, MD, MBA; Robin K. (“Katie”) Kelley, MD; Professor Riccardo Lencioni, MD, FSIR, EBIR; and Amit Singal, MD, MS • Thank you to Medical Learning Institute, Inc. and PeerView Institute for Medical Education for developing this educational event, and to Bayer Healthcare Pharmaceuticals Inc., Celsion Corporation, and Exelixis, Inc. for providing the educational grants for this symposium • Please silence your cell phones • If you haven’t already, please complete the pre-event/lunch survey • Reminder: Look out for additional follow-up polling on your iPads • Submit your questions on your iPad and we will answer them during the Q&A session

3. Faculty Disclosures • Chair • Ghassan Abou-Alfa, MD, MBAMemorial Sloan Kettering Cancer Center • Weill Medical College at Cornell University • New York, New York • Ghassan Abou-Alfa, MD, MBA, has a financial interest/relationship or affiliation in the form of: • Consultant and/or Advisor for 3D Medicines Corporation; Agios, Inc.; Alignmed; Amgen Inc.; AstraZeneca; Bayer; BeiGene; Boston Scientific Corporation; BridgeBio Inc.; Bristol-Myers Squibb; CARsgen Therapeutics; CASI Pharmaceuticals Inc.; Celgene Corporation; Cipla Inc.; Daiichi Sankyo Company, limited; Debiopharm Group; Delcath Systems Inc.; Eisai Inc.; Eli Lilly and Company; Exelixis, Inc.; Flatiron; Genoscience Pharma; Halozyme, Inc.; Hengrui Therapeutics, Inc.; Incyte Corporation; Inovio Pharmaceuticals, Inc.; Ipsen Biopharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Klus Pharma Inc; Kyowa Kirin, Inc.; LAM Inc.; Merck & Co., Inc.; MINAPHARM Pharmaceuticals; Novella; Onxeo; PCI Biotech; QED Therapeutics; Redhill; sanofi-aventis U.S. LLC; Servier; SillaJen, Inc.; Tekmira; twoXAR; VIVUS Inc.; Yakult Pharmaceutical Industry Co., Ltd.; and Yiviva.Grant/Research Support from ActaBiologica; Agios, Inc.; Array BioPharma; AstraZeneca; Bayer; BeiGene; Bristol-Myers Squibb; CASI Pharmaceuticals Inc.; Celgene Corporation; Eli Lilly and Company; Exelixis, Inc.; F. Hoffmann-La Roche Ltd; Genentech, Inc.; Halozyme, Inc.; Incyte Corporation; MabVax Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; OncoQuest Inc.; Polaris Puma; and QED Therapeutics.Other financial interest/relationship Spouse consulting for: Bioline; Celgene Corporation; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Loxo Oncology; Merck & Co., Inc.; Pfizer Inc.; Silenseed LTD; Sobi, Inc; Targovax; and twoXAR. This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.This activity is supported by medical educational grants from Bayer Healthcare Pharmaceuticals Inc., Celsion Corporation, and Exelixis, Inc.

4. Faculty Disclosures • Presenter • Robin K. (“Katie”) Kelley, MDHelen Diller Family Comprehensive Cancer Center • University of California, San Francisco • San Francisco, California • Robin K. (“Katie”) Kelley, MD, has a financial interest/relationship or affiliation in the form of: • Other financial interest/relationship Investigator on Clinical Trials for Adaptimmune; Agios, Inc.; AstraZeneca; Bayer; Bristol-Myers Squibb; Eli Lilly and Company; Exelixis, Inc.; MedImmune; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; QED Therapeutics; and Taiho oncology, Inc. lOMC member of Genentech, Inc./ F. Hoffmann-La Roche Ltd. This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.This activity is supported by medical educational grants from Bayer Healthcare Pharmaceuticals Inc., Celsion Corporation, and Exelixis, Inc.

5. Faculty Disclosures • Presenter • Professor Riccardo Lencioni, MD, FSIR, EBIRUniversity of PisaPisa, ItalyMiami Cancer InstituteMiami, Florida • Professor Riccardo Lencioni, MD, FSIR, EBIR, has a financial interest/relationship or affiliation in the form of: • Other financial interest/relationship Consultant and/or Advisor for​: AstraZeneca and Celsion, Inc. This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.This activity is supported by medical educational grants from Bayer Healthcare Pharmaceuticals Inc., Celsion Corporation, and Exelixis, Inc.

6. Faculty Disclosures • Presenter • Amit Singal, MD, MSUT Southwestern Medical CenterDallas, Texas • Amit Singal, MD, MS, has a financial interest/relationship or affiliation in the form of: • Consultant and/or Advisor for Bayer Corporation; Bristol-Myers Squibb; Eisai Inc.; and Exelixis, Inc.Other financial interest/relationship for Target MCC for Steering Committee. This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.This activity is supported by medical educational grants from Bayer Healthcare Pharmaceuticals Inc., Celsion Corporation, and Exelixis, Inc.

7. Planning Committee Disclosures • The planners from Medical Learning Institute, Inc., the accredited provider, and PVI, PeerViewInstitute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this CME/MOC activity during the past 12 months unless listed below.

8. Content Reviewer Disclosures • Content Review • The following Content Reviewers have nothing to disclose: • Steve S. Choi, MD • Teresa Haile, RPh, MBA

9. Disclosure of Unlabeled Use This educational activity may contain discussions of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

10. Visit us atPeerView.com/Liver19 • Watch for the onDemand version in the coming weeks • Download the slides and Practice Aids • Apply for CME/MOC credit Need more information? Send an email to live@PeerView.com Join the conversation on Twitter @PeerView

11. Welcome and Introduction:The Evolving Therapeutic Management of HCC GhassanAbou-Alfa, MD, MBAMemorial Sloan Kettering Cancer Center Weill Medical College at Cornell University New York, New York Go online to access full CME/MOC information, including faculty disclosures.

12. Projections of HCC Incidence Into 20301 Male HCC Incidence Rates 60 Rate per 10,000 Person-Years Overserved Projected 50 Hispanic Black 40 All males White 30 Asian 20 10 0 2025 2030 2015 2010 2005 2000 2020 Year of Diagnosis 1. Petrick JL et al. J Clin Oncol. 2016;34:1787-1794.

13. Mortality From Cancer According to Body Mass Index (BMI) for US Men1,2 Men Type of Cancer (Highest BMI Category) 1.34 Prostate (≥35) 1.49 Non-Hodgkin lymphoma (≥35) 1.52 All cancers (≥40) 1.68 All other cancers (≥30) 1.70 Kidney (≥35) 1.71 Multiple myeloma (≥35) 1.76 Gallbladder (≥30) 1.84 Colon and rectum (≥35) 1.91 Esophagus (≥30) 1.94 Stomach (≥35) 2.61 Pancreas (≥35) 4.52 Liver (≥35) 0 1 2 3 4 5 6 7 Relative Risk of Death (95% CI) 1. https://www.cancer.org/research/we-conduct-cancer-research/epidemiology/cancer-prevention-study-2.html. Accessed September 12, 2019. 2. Calle EE et al. N Engl J Med. 2003;348:1625-1638.

14. Child–Pugh Score of Liver Cirrhosis1 1. Pugh RN et al. Br J Surg. 1973;60:646-649.

15. Barcelona Clinic Liver Cancer Staging1 HCC ECOG 0-2, Child A-B ECOG >2, Child C ECOG 0, Child A Very early stage, single <2 cm Early stage, ≤3 nodules, <3 cm, ECOG 0 Intermediate stage,multinodular, ECOG 0 Advanced stage, portal invasion, N1, M1, ECOG 1-2 Terminal stage Single 3 nodules, ≤3 cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes Chemoembolization Sorafenib Resection Transplant PEI/RFA Curative Treatments Palliative Options BSC 1. Adapted from Forner A et al. Semin Liver Dis. 2010;30:61-74.

16. Today’s Agenda Tumor Board and MasterClass: Each speaker will present patient cases to illustrate the complexities of treatment decision-making and to effectively integrate multidisciplinary care strategies based on clinical evidence • Amit Singal, MD, MS, on selecting and sequencing TKIs across the continuum of care in advanced HCC • Katie Kelley, MD, on newer targeted and immunotherapy options as second-line treatment and beyond • Prof. Riccardo Lencioni, MD, FSIR, EBIR, on expanding the therapeutic arsenal in earlier-stage disease

17. Choosing and Sequencing TKIs Across the Continuum of Care in Advanced HCC Amit Singal, MD, MSUT Southwestern Medical Center Dallas, Texas Go online to access full CME/MOC information, including faculty disclosures.

18. Tumor Board 1: 57-Year-Old Male With NASH Cirrhosis • Metabolic syndrome with diabetes complicated by stage 2 nephropathy and hypertension • Child–Pugh A: bilirubin 0.6, albumin 3.4, INR 1.1; no ascites or encephalopathy • AFP 247 ng/mL • ECOG PS 0 • MRI shows multifocal HCC (LR-5) with 4 lesions • The largest is 6 cm, and all 4 are in the right lobe • No evidence of vascular invasion or distant metastases

19. Tumor Board 1: 57-Year-Old Male With NASH Cirrhosis (Cont’d) • Treated with TARE; stable disease on follow-up imaging • Treated with TACE with disease progression, including new tumor thrombus in the main portal vein Dr. Singal – to add images

20. Tumor Board 1 Discussion:Modified BCLC Staging System 20181 HCC in cirrhotic liver Very early stage (0) Single <2 cm Preserved liver function PS 0 Early stage (A) Single or 2-3 nodules <3 cm Preserved liver function PS 0 Intermediate stage (B) Multinodular, unresectable Preserved liver function PS 0 Advanced stage (C) Portal invasion/ extrahepatic spread, Preserved liver function PS 1-2 Terminal stage (D) Not transplantable End-stage liver function PS 3-4 Solitary 2-3 nodules ≤3 cm Optimal surgical candidate Transplant candidate Yes No Yes No Ablation Resection Transplant Ablation Chemoembolization Systemic therapy BSC 3 mo >5 y >2.5 y ≥10 mo 1. Galle PR et al. J Hepatol. 2018;69:182-236.

21. Tumor Board 1 Discussion:Frontline Options1 1. Galle PR et al. J Hepatol. 2018;69:182-236.

22. Phase 3 SHARP Trial:Sorafenib vs Placebo in Advanced HCC1 Overall Survival Stratification • Macroscopic vascular invasion (portal vein) and/or EHS • ECOG PS • Geographic region Sorafenib 400 mg orally twice daily continuous dosing (n = 299) N = 602a R Placebo 2 tablets orally twice daily continuous dosing (n = 303) HR = 0.69 (95% CI, 0.55-0.87) P = .00058 Sorafenib OS = 10.7 mo Placebo OS = 7.9 mo a Majority of patients were Child–Pugh A. 1. Llovet JM et al. N Engl J Med. 2008;359:378-390.

23. GIDEON Study: Tolerability in Child–Pugh A and B1 Sorafenib safety results during treatment are generally consistent across patients irrespective of liver function a Includes Child–Pugh C, 74 patients; NE, 493 patients. b Treatment emergent. c Calculated based on 365.25 days per year. d Patients with dosing data. 1. Marrero JA et al. J Clin Oncol. 2013;31:15(suppl): Abstract 4126.

24. REFLECT Phase 3 Trial:Lenvatinib vs Sorafenib in the First Line1 Global, randomized, open-label, phase 3, noninferiority study • Primary endpoint:OS • Secondary endpoints: PFS, TTP, ORR, QOL, and PK lenvatinib exposure parameters • Tumor assessments were performed according to mRECIST by the investigator • Patients with unresectable HCC • No prior systemic therapy for unresectable HCC • ≥1 measurable target lesion per mRECIST • BCLC stage B or C • Child–Pugh A • ECOG PS ≤1 • Adequate organ function • Patients with ≥50% liver occupation, clear bile duct invasion, or portal vein invasion at the main portal vein were excluded Lenvatinib 8 mg (body weight <60 kg) or 12 mg (body weight ≥60 kg) once daily (n = 478) • Stratification • Region (Asia-Pacific or Western) • MVI and/or EHS (yes or no) • ECOG PS (0 or 1) • Body weight (<60 kg or ≥60 kg) N = 954 R Sorafenib 400 mg twice daily (n = 476) 1. Kudo M et al. Lancet. 2018;391:1163-1173.

25. REFLECT Primary Endpoint: Noninferior OS Compared With Sorafenib1 1. Kudo M et al. Lancet. 2018;391:1163-1173.

26. REFLECT Secondary Endpoint: Kaplan–Meier Estimate of PFS1 1. Kudo M et al. Lancet. 2018;391:1163-1173.

27. Lenvatinib Had a Significantly Increased Objective Response Rate Compared With Sorafenib1 1. Kudo M et al. Lancet. 2018;391:1163-1173.

28. Adverse-Event Profile Differs Between Sorafenib and Lenvatinib1 1. Kudo M et al. Lancet. 2018;391:1163-1173.

29. Considerations When SelectingFirst-Line Treatment Options

30. Tumor Board 1: 57-Year-Old Male With NASH Cirrhosis (Cont’d) • Started on sorafenib 400 mg daily for 2 weeks and then increased to full dose of 400 mg BID • At 2 months, developed grade 2 hand-foot skin reaction • What would you do next? • Sorafenib held until resolution • Then restarted at 400 mg daily and increased back to 400 BID, as he did well over time

31. Tumor Board 1: 57-Year-Old Male With NASH Cirrhosis (Cont’d) • Stable disease at 3, 6, and 9 months • Then noted to have new pulmonary metastases at 12 months • Child–Pugh A: bilirubin 0.9, albumin 3.2, INR 1.2; no ascites or encephalopathy • AFP 215 ng/mL • ECOG PS 0 What would be appropriate treatment options for this patient?

32. Tumor Board 1 Discussion:Second-Line Options1 Advanced stage (BCLC stage C: portal invasion and/or EHS) Intermediate stage (BCLC stage B: multinodular) progressing on LRTs First Line PD SecondLine 1. Llovet JM et al. Nat Rev Clin Oncol. 2018;15:599-616.

33. RESORCE: Regorafenib vs Placebo in the Second-Line Setting1 • Primary endpoint:OS • Secondary endpoints:PFS, TTP, response rate, and DCR • 152 centers in 21 countries in North and South America, Europe, Australia, and Asia • All patients received BSC • Patients were treated until disease progression, death, or unacceptable toxicity Regorafenib 160 mg orally; 3 weeks on, 1 week off (4-week cycle) (n = 379) • Stratification • Geographic region (Asia vs rest of the world) • MVI • EHD • ECOG PS (0 vs 1) • AFP (< or ≥400 ng/mL) • HCC with documented radiologic progression during sorafenib treatment N = 573 2:1 R Placebo (n = 194) 1. Bruix J et al. Lancet. 2017;389:56-66.

34. Regorafenib Improves Overall Survival in the Second-Line Setting1 Regorafenib Placebo a Based on mRECIST. 1. Bruix J et al. Lancet. 2017;389:56-66.

35. Regorafenib Survival Benefit Consistent Across Subgroup Analyses1 1. Bruix J et al. Lancet. 2017;389:56-66.

36. Treatment-Emergent AE Profile1 1. Bruix J et al. Lancet. 2017;389:56-66.

37. Sequencing Systemic Therapies Can Provide Meaningful Survival Exceeding 2 Years1,2 n = 374 n = 374 n = 193 n = 193 n = 143 n = 143 n = 73 n = 73 n = 231 n = 120 n = 231 n = 120 Regorafenib Placebo 1. Finn RS et al. 2017 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2017). Abstract 344. 2. Finn RS et al. J Hepatol. 2018;69:353-358.

38. On Your iPad Answer Questions Please take a few moments to answer a follow-up question regarding TKI therapies for HCC before we move on

39. Conclusions • Sorafenib and lenvatinib are both approved options for first-line treatment of patients with unresectable HCC • There are subtle differences in inclusion criteria, efficacy, and adverse event profiles that can help us decide between two agents • There are multiple options for second-line treatment of patients who are intolerant or have disease progression on first-line therapy • Regorafenib: RESORCE trial showed superiority over placebo • Using agents in sequence can result in a meaningful survival benefit • Studies are needed to identify treatment-response biomarkers to select the ideal sequence of treatments for individual patients

40. Newer Targeted and Immunotherapy Options as Second-Line Treatment and Beyond Robin K. (“Katie”) Kelley, MDHelen Diller Family Comprehensive Cancer Center University of California, San Francisco San Francisco, California Go online to access full CME/MOC information, including faculty disclosures.

41. Tumor Board 2:62-Year-Old Male With Chronic HBV • Asian male with chronic HBV on entecavir with undetectable viral load • Child–Pugh A, platelets 259, ECOG 0 • Screening AFP showed new elevation to 58 ng/mL; was normal 12 months earlier • MRI showed 14-cm right lobe tumor, HCC (LR-5), with 2 satellite lesions; diminutive left lobe • No evidence of vascular invasion or distant metastases • Treated with TARE with tumor necrosis but new tumor thrombus in main portal vein and multiple new bilateral pulmonary nodules • Started on sorafenib 400 mg twice daily (standard dose) • Developed redness and discomfort of palms and soles after 2 weeks, blistering at 3 weeks despite optimal hand-foot skin care; required treatment delay then dose reduction after 3 weeks • Patient did not tolerate sorafenib despite dose reduction and delays due to grade 3 hand-foot skin reaction and had to discontinue • AFP 283 ng/mL • ECOG PS 0

42. Tumor Board 2 Discussion:Multiple Options Beyond First-Line Therapy1 Advanced stage (BCLC stage C: portal invasion and/or EHS) Intermediate stage (BCLC stage B: multinodular) progressing on LRTs First Line PD SecondLine 1. Llovet JM et al. Nat Rev Clin Oncol. 2018;15:599-616.

43. CELESTIAL: Cabozantinib vs PlaceboAfter Prior Sorafenib1 • Primary endpoint:OS • Secondary endpoints:PFS and ORR Cabozantinib 60 mg/d • Stratification • Disease etiology (HBV, HCV, other) • Region (Asia, other) • Presence of MVI and/or EHS of disease (yes or no) • Advanced HCC; Child–Pugh A • ECOG PS 0-1 • Prior sorafenib • Progression on ≥1 prior therapy • ≤2 prior therapies N = 760 2:1 R Placebo All patients had previously received sorafenib, and 27% had received two previous systemic anticancer regimens for advanced HCC 1. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63.

44. Cabozantinib Improves Overall Survival in the Second- or Third-Line Setting1 a January 2019: Cabozantinib was approved for use in patients with advanced HCC previously treated with sorafenib a Critical P ≤ .021 for second interim analysis. 1. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63.

45. Cabozantinib Improves Progression-Free Survival in the Second- or Third-Line Setting1 ORR: cabozantinib 4% vs placebo 0.4% (P = .0086) PR or SD: cabozantinib 64% vs placebo 33% 1. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63.

46. Cabozantinib Survival Benefit Consistent Across Subgroup Analyses1 1. Abou-Alfa G et al. N Engl J Med. 2018;379:1384-1385. 1 0.1 0.2 2 0.25 0.25 0.5 0.5 Favors placebo Favors placebo Favors cabozantinib Favors cabozantinib

47. All-Causality Grade 3 or 4 AEs1,a • Grade 5 TRAEs • Cabozantinib (n = 6): hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper GI hemorrhage, pulmonary embolism, and hepatorenal syndrome • Placebo (n = 1): hepatic failure a Grade 3/4 events reported in at least 5.0% of patients in either treatment group. 1. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63.

48. Tumor Board 2 Discussion:62-Year-Old Male With Chronic HBV, cont. • Started cabozantinib with empiric starting dose reduction to 40 mg daily; AFP 283 ng/mL • Required dose reduction to 20 mg daily after 2 weeks due to abdominal cramping and diarrhea • Restaging CT after 2 and 4 months showed tumor regression; AFP declined to nadir of 137 ng/mL • Restaging CT after 6 months showed tumor progression with new ascites, elevated bilirubin, AFP elevation to 400 ng/mL; discontinued cabozantinib; required paracentesis and transitioned to palliative care

49. Tumor Board 3:64-Year-Old Male With HCV Cirrhosis • Metabolic syndrome with diabetes complicated by stage 2 nephropathy and hypertension • Child–Pugh A: bilirubin 1.2, albumin 3.1, INR 1.1; no ascites or encephalopathy • AFP 247 ng/mL • ECOG PS 0 • MRI showed multifocal HCC (LR-5) with 4 lesions (the largest was 6 cm), and hepatic vein tumor thrombus • Treated with multiple TACE over 2 years • Developed disease progression including rib, nodal, and adrenal metastases • Received palliative RT to painful rib metastasis • Started on sorafenib 400 mg BID • Required augmented antihypertensive regimen • Grade 1-2 hand-foot syndrome and loose stools • Had stable disease and AFP declined to nadir 120 ng/mL over 6 months, then developed rising AFP and progression in adrenal, nodal, and rib metastases • AFP 1,054 ng/mL • ECOG PS 0

50. Tumor Board 3 Discussion:Multiple Options Beyond First-Line Therapy1 Advanced stage (BCLC stage C: portal invasion and/or EHS) Intermediate stage (BCLC stage B: multinodular) progressing on LRTs First Line PD SecondLine 1. Llovet JM et al. Nat Rev Clin Oncol. 2018;15:599-616.