Hepatocellular CarcinomaAbby Siegel MD, MS

Columbia University

Co-Chair, SWOG Hepatobiliary Committee

NCI Task Force, Hepatobiliary Cancers

Outline

• Epidemiology

• Biology

• Staging/Prognosis/Management

• Future of Targeted Therapy

Outline

• Epidemiology

• Biology

• Staging/Prognosis/Management

• Future of Targeted Therapy

El-Serag and Rudolph, Gastroenterology, 2007

Liver Cancer Mortality Worldwide

• Colon cancer• Gastric cancer• Pancreatic cancer• Hepatobiliary cancers

HCC Incidence and Death Rates are Increasing in the US

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

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

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?

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

Mortality from cancer according to BMI…

Outline

• Epidemiology

• Biology

• Staging/Prognosis/Management

• Future of Targeted Therapy

Pathway Alterations in HCC

Han et al, Ann Rev Genomics and Human Genetics, 2012

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

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

Clinical Applications of HCC Sequencing

Sung et al, Nature Genetics, 2012 44:765 Arao et al, Hepatology, 2013 57:1407

HBV integrations related to worsened survival after resection

FGF3/FGF4 amplifications seen in responders to sorafenib

Outline

• Epidemiology

• Biology

• Staging/Prognosis/Management

• Future of Targeted Therapy

Llovet et al. J. Natl. Cancer Inst. 2008 100:698-711

Barcelona Clinic Liver Cancer (BCLC) Staging Classification

<1 cm>1 cm

Liver lesion in a cirrhotic

4 phase CT or dynamic contrast enhanced MRI

Repeat US 3 months

Arterial hypervascularityand venous or delayed

phase washout

Another scan,(Different modality)

Growing/changing

Stable

Yes No

NoYes

HCCInvestigate

according to size

Arterial hypervascularityand venous or delayed

phase washout

Biopsy

AFP is no longer needed for diagnosis!

Workup of Liver Mass in Cirrhosis

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 2007 13:851-857, Kim et al, Int J Rad Onc Biol Phys 2007 69:3, 813-819

Cirrhosis and HCC

Macronodular: HBV, autoimmune

Micronodular: HCV, NASH, ETOHNormal liver

HCC with cirrhosis

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, 334:693-700

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

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)

RFA (Radiofrequency Ablation)

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

Chemoembolization

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

Advanced Disease:Chemotherapy Historically Disappointing

• Difficult to give chemotherapy with liver compromise

• Overexpression of MDR-1 gene

• Targets until now have been poorly defined

Molecularly Targeted Therapy for HCC

Modified from Siegel et al, Hepatology 52:360-369, 2010

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)

Unresectable and/or metastatic HCC

No prior therapy

N=602

Arm A: Sorafenib

Arm B: Placebo

Llovet et al, N Engl J Med 359:378-390, 2008

Overall Survival Increased from 7.9 to 10.7 months in Treated Group

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)

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

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

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

Problems With These Trials

• Based on non-randomized phase II data

• Significant heterogeneity of patient populations (etiology, region, etc)

• No predictive biomarkers!

Outline

• Epidemiology

• Biology

• Staging/Prognosis/Management

• Future of Targeted Therapy

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

Hepatocyte Growth Factor (HGF)/MET Pathway

Appleman L J JCO 2011;29:4837-4838

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

Clinical Activity of MET Inhibition

Rimassa et al, ASCO 2012

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

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

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 (-)

• 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!