Hepatocellular Carcinoma

1. Hepatocellular Carcinoma Abby Siegel MD, MS Columbia University Co-Chair, SWOG Hepatobiliary Committee NCI Task Force, Hepatobiliary Cancers

2. Outline • Epidemiology • Biology • Staging/Prognosis/Management • Future of Targeted Therapy

3. Outline • Epidemiology • Biology • Staging/Prognosis/Management • Future of Targeted Therapy

4. Liver Cancer Mortality Worldwide El-Serag and Rudolph, Gastroenterology, 2007

5. Colon cancer • Gastric cancer • Pancreatic cancer • Hepatobiliary cancers

6. HCC Incidence and Death Rates are Increasing in the US

7. HCC Risk Factors • Exposures • HCV, ETOH, Aflatoxin • HBV • HBV viral load>104 copies/ml, genotype C, e antigen positive • Genetic susceptibility • hereditary hemochromatosis, alpha-1 antitrypsin deficiency, Wilson’s disease • Metabolic factors • NASH, metabolic syndrome • Demographics • Older age, male sex

8. Impact of NAFLD • Up to 30% of the US population has fatty liver disease: the “hepatic manifestation” of metabolic syndrome • This can progress to inflammation, known as non-alcoholic steatohepatitis (NASH) • NASH contributes to up to a third of HCCs in this country, and incidence is increasing • Those with features of metabolic syndrome also have worse outcomes from several kinds of cancer Siegel et al, Cancer 2009 115:5651-5661

9. Potential Reasons for Worse Outcomes Unclear… • Screened differently? • Comorbidity? • Biological hypothesis? • Dietary obesity promotes HCC in mice • Increased BMI may be associated with increased vascular invasion • Can we modulate these risk factors for both prevention and treatment with statins/metformin? Mortality from cancer according to BMI… Calle EE et al. N Engl J Med 2003;348:1625, Park et al, Cell 2010, 140:197, 2010 , Siegel et al, Transplantation 2012, 94:539, Tsan et al, JCO 2013 31:1514, Siegel JCO 2013 31:1499, Zhang et al, Scan J Gastro 2013, 48:78

10. Outline • Epidemiology • Biology • Staging/Prognosis/Management • Future of Targeted Therapy

11. Pathway Alterations in HCC Han et al, Ann Rev Genomics and Human Genetics, 2012

12. Sequencing of HCC • Wnt-B-catenin, TP53 most commonly altered • p53 activator and WNT tx in phase I trials • Chromatin remodeling genes also altered • Sequence of fibrolamellar hepatocellular carcinomas related to a 400 kb deletion on chromosome 19 leading to novel fusion of DNAJB1 and PRKACA Guichard et al, Nature Genetics 44:694-98 2012,Honeyman et al, Science 2014, 343:6174

13. Major pathways altered in hepatocellular carcinoma. Signaling pathways recurrently mutated in HCC are shown in the right panel. Oncogenes are indicated in red and tumor-suppressor genes in blue with percentages of alterations. Nault et al. J. Hepatology, 2014, 60:224-226

14. Clinical Applications of HCC Sequencing • HBV integrations related to worsened survival after resection • FGF3/FGF4 amplifications seen in responders to sorafenib Sung et al, Nature Genetics, 2012 44:765 Araoet al, Hepatology, 2013 57:1407

15. Outline • Epidemiology • Biology • Staging/Prognosis/Management • Future of Targeted Therapy

16. Barcelona Clinic Liver Cancer (BCLC) Staging Classification Llovet et al. J. Natl. Cancer Inst. 2008 100:698-711

17. Liver lesion in a cirrhotic Workup of Liver Mass in Cirrhosis <1 cm >1 cm 4 phase CT or dynamic contrast enhanced MRI Repeat US 3 months Growing/ changing Stable Arterial hypervascularity and venous or delayed phase washout Yes Another scan, (Different modality) No Investigate according to size HCC Arterial hypervascularity and venous or delayed phase washout Biopsy AFP is no longer needed for diagnosis! Yes No

18. Chemotherapy can Reactivate HBV • Guidelines vary • If ag positive, treat with antiviral before and after tx • Prevalence of HBV in DR and parts of Asia=15%-25% • Not unreasonable to test everyone • Risk of reactivation 20%-50% with chemo • Core (+) patients can also reactivate, although at lower rates • HBV reactivation in 22% of those getting 3D CRT* • Get hepatology involved if questions Chou et al, ClinCanc Res 2007 13:851-857, Kim et al, Int J Rad OncBiolPhys 2007 69:3, 813-819

19. Cirrhosis and HCC Normal liver Micronodular: HCV, NASH, ETOH HCC with cirrhosis Macronodular: HBV, autoimmune

20. Milan Criteria for Liver Transplantation • If only one tumor, it must be 5 cm or less • 3 or fewer tumors, each 3 cm or less • No gross vascular invasion Mazzafero et al. NEJM1996, 334:693-700

21. Resection • Consider resection in: • Non-cirrhotics (often those with HBV!) • Compensated cirrhotics (normal bilis and hepatic venous pressure gradient <10 mm hg) • Only 10-20% of those in the West are candidates for resection

22. Local Therapies • RFA • Nonrandomized data suggest outcomes as good as resection for small (<2 cm) lesions • Embolization (bland, chemo, Y90) • Metaanalyses suggest benefit in well-selected patients for embolization c/w placebo • Y90 better for PVT, but can do fewer tx due to radiation toxicity • External beam radiation • Exciting, awaiting randomized trials (RTOG 1112)

23. RFA (Radiofrequency Ablation)

24. Chemoembolization (TACE) • The normal liver receives most of its blood supply through the portal vein, and only about 25 percent from the hepatic artery • Tumors receive almost all of their blood supply from the hepatic artery • “Dual therapy” using both embolization and chemotherapy • Now also using Y90: radiolabeled beads

25. Chemoembolization

26. Review of Chemoembolization • Overall survival advantage seen with chemoembolization • Approximately ½ the risk of death with two year follow up • Response rates in 35% of patients • Highly selected patients Llovet and Bruix, Hepatology 2003; 37:429-422

27. Advanced Disease:Chemotherapy Historically Disappointing • Difficult to give chemotherapy with liver compromise • Overexpression of MDR-1 gene • Targets until now have been poorly defined

28. Molecularly Targeted Therapy for HCC Modified from Siegel et al, Hepatology 52:360-369, 2010

29. Phase III Trial of Sorafenib (Bay 43-9006) In First-Line Advanced HCC • Randomized phase III trial comparing sorafenib vs. placebo for previous untreated HCC: Sorafenib HCC Assessment Randomized Protocol (SHARP) Arm A: Sorafenib Unresectable and/or metastatic HCC No prior therapy N=602 Arm B: Placebo Llovet et al, N Engl J Med 359:378-390, 2008

30. Overall Survival Increased from 7.9 to 10.7 months in Treated Group

31. Grade 3-4 Toxicities of Sorafenib • Hand-foot reaction 21% • Randomized trial suggests benefit with up-front urea cream 20% • Diarrhea 39% • Anorexia 14% • Bleeding 7% (p=0.07)

32. Limited Data for Sorafenib in CP B: GIDEON • International registry • Interim analysis: 1586 patients • 23% CP B • Overall survival short (5 months) • No significant differences in adverse events attributable to sorafenib between CPA and CPB patients Lencioni, ASCO 2011, Chicago Il

33. Dosing Sorafenib for Hepatic Dysfunction • CALGB 60301 • T. Bili up to 1.5 x ULN • Full dose (400 mg BID) ok • T Bili up to 3 x ULN: • Half dose (200 mg BID) ok • T Bili > 3 x ULN: • Not even 200 q 3 days tolerable Miller et al, JCO 2009; 27:1800-5

34. Other Options? Randomized Trials in Advanced HCC so far NEGATIVE • First Line: • Sunitinib, brivanib, erlotinib+sorafenib, linifinib • Second line • Brivanib: improved PFS with mRECIST, trend toward OS with imbalances favoring placebo • One possible exception first-line: EACH • FOLFOX vs Doxorubicin: “close” p value (p=0.07, later updated to 0.04) • Asian population, some imbalances in arms favoring FOLFOX Cheng et al, JCO 2013, Johnson, et al. JCO 2013, Zhu et al, submitted, Cainap et al, ASCO 2012, Llovet et al, JCO 2013, Qin et al, JCO 2013

35. Problems With These Trials • Based on non-randomized phase II data • Significant heterogeneity of patient populations (etiology, region, etc) • No predictive biomarkers!

36. Outline • Epidemiology • Biology • Staging/Prognosis/Management • Future of Targeted Therapy

37. C-Met Inhibitors • Proto-oncogene important for embryogenesis and wound healing • Overexpressed in 20-50% of HCC • Poor prognostic marker • Very “druggable” at ligand or TK

38. Hepatocyte Growth Factor (HGF)/MET Pathway Appleman L J JCO 2011;29:4837-4838

39. C-MET Inhibition • Several drugs: • Cabozantinib (combo VEGFR/c-MET TKI) • Tivantinib (“pure” c-MET TKI-? other effects) • C-MET expression emerging as possible predictive and prognostic biomarker… • Those who express it do worse but • They may respond better to c-MET inhibition

40. Clinical Activity of MET Inhibition Rimassa et al, ASCO 2012

41. Other Potential Avenues for Targeted Therapy… • Delve further into anti-angiogenics • Ramucirumab, lenvatinib • mTOR inhibition • Predictive biomarkers pending • Dual inhibitors (metformin, CC-223) • Immune therapies • CTLA-4, PD-1, PDL1 abs • Targeting stem cells: • WNT targeted decoy receptor (OMP-54F28) • Methylation pathways • SGI 110

42. Sorafenib Combinations • TACE + sorafenib: data NEGATIVE so far (Asia, SPACE) • Two studies pending: ECOG 1208, British TACE-2 • STORM • Treating high risk patients after local therapy or resection for up to 4 years: NEGATIVE • Post-transplant • Multicenter Phase I trial of high-risk HCC patients completed at Columbia: MTD 200 BID

43. Ongoing Phase III Trials • First Line: • Sor+/- Doxorubicin • Sor vs Lenvantinib • Second Line: • Ramucirumab vs BSC • ADI-PEG vs BSC • Tivantinib vs BSC • Regorafenib vs BSC • Multi-modality: • Sor +/- SBRT, Sor +/-TACE, Sor vs Y90 • Adjuvant STORM reportedly (-)

44. We’ve made progress, but still have a long way to go… • Recognize those who may be curable • Encourage enrollment on clinical trials • Continue search for new biomarkers!