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 Genetic susceptibility Metabolic factors
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 :

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 :1514, Siegel JCO :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: , Honeyman et al, Science 2014, 343:6174

13. Major pathways altered in hepatocellular carcinoma
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:

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, : Arao et al, Hepatology, :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 :

17. Workup of Liver Mass in Cirrhosis
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, Clin Canc Res : , Kim et al, Int J Rad Onc Biol Phys :3,

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. NEJM 1996, 334:

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:

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: , 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: , 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:

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!