Hepatobiliary Cancers Tel: (202) 444-0275 | Fax: (202) 444-1229 Hepatobiliary Cancers http://lombardi.georgetown.edu/GI John L. Marshall, MD Professor Director, Otto J. Ruesch Center at Lombardi Comprehensive Cancer Center Chief, Division of Hematology/Oncology, Georgetown University Hospital Associates 1

NATURE | OUTLOOK A preventable cancer Nature 516, S2–S3 (04 December 2014) doi:10.1038/516S2a 03 December 2014 Liver cancer is difficult to treat, and lethal if not caught early. But its most common causes, such as hepatitis viruses and obesity, can be prevented. OUT OF PROPORTION Not only does liver cancer strike more men than women, it also causes a disproportionate number of cancer-related deaths. Although it is the sixth most common malignancy worldwide, it is second only to lung cancer in terms of mortality Nature | Outlook A preventable cancer Lucas Laursen Journal name: Nature Volume: 516, Pages: S2–S3 Date published: (04 December 2014) DOI: doi:10.1038/516S2a Published online 03 December 2014

DOMINANT SUBTYPE Liver cancer has several subtypes, but one — hepatocellular carcinoma (HCC) — is by far the most common worldwide. In some countries, the proportion of subtypes differs as a result of different risk factors

RISK ASSESSMENT Liver-cancer rates vary widely between countries, with the highest rates occurring in Africa and east Asia. The disease is nearly always preceded by chronic liver damage, most commonly caused by hepatitis B. Highlighted below are other common causes in selected countries

HCC may be prevented. A SUCCESS STORY Liver disease takes decades to progress to cancer, which makes prevention research difficult. In Japan, a 30-year gap separated the peak of hepatitis infections (both HBV and HCV) and the resulting rise in liver cancer15. But public-health efforts on multiple fronts are bringing liver-cancer rates back down16

This slide highlights the groups for whom HCC screening and surveillance is recommended or in whom the risk of HCC is increased, although efficacy of surveillance programs has not been fully demonstrated in prospective trials The group of chronic HBV patients without cirrhosis had the lowest % incidence of HCC/year Patients with hep B and C cirrhosis who have cleared virus, still have a risk for HCC, albeit reduced Reference: Bruix J, et al. Hepatology. 2011;53(3):1020-1022.

This slide lists 5 societies/groups for whom surveillance guidelines are published AASLD and EASL both recommend ultrasound examinations every 6 months The recently-updated EASL guidelines also specify that for some patients with suspicious nodules, surveillance intervals may need to be increased to every 3 to 4 months Alpha-fetoprotein is no longer recommended by either the EASL or AASLD, but still included in the APASL, NCCN, and VA guidelines to date References: Bruix J, et al. Hepatology. 2005;42:1208-1236. Bruix J, et al. Hepatology. 2011;53(3):1020-1022. Llovet JM, et al. J Hepatol. 2012;56(4):908-943. Omata M, et al. Hepatol Int. 2010;4:439-474. Adapted from NCCN Practice Guidlelines in Oncology. Hepatocellular Carcinoma v2.2012. Available at: http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed August 22, 2012. US Dept of Veterans Affairs. Available at: http://www.hepatitis.va.gov/pdf/2009HCC-guidelines.pdf. Accessed August 22, 2012.

Sorafanib Multidisciplinary Management The management of HCC is challenging due to the underlying liver disease (eg, HBV, HCV), variable biologic behavior and morphology, and variations in local expertise and available resources. Reference: Rilling WS, Drooz A. J Vasc Interv Radiol. 2002;13(9 pt 2):S259-S263. Sorafanib

Barcelona Clinic Liver Cancer Staging and Treatment Strategy Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule Stage 0 HCC patients are optimal candidates for resection Stage A, early HCC, patients are candidates for radical therapy (resection, liver transplantation [LT], or local ablation via percutaneous ethanol injection [PEI] or radiofrequency [RF] ablation) Stage B, intermediate HCC, patients benefit from transarterial chemoembolization (TACE) Stage C, advanced HCC, patients are patients with macroscopic vascular invasion, extrahepatic spread, or cancer-related symptoms (Eastern Cooperative Oncology Group performance status 1 or 2) these patients benefit from Nexavar Stage D, end stage patients will receive symptomatic treatment Reference Llovet JM, et al. J Natl Cancer Inst . 2008;100:698–711

Surgical Resection Surgical resection is best suited for HCC patients who have a single HCC nodule, Child-Pugh A, and who do not have significant portal hypertension (HVPG <10 mg Hg) Five year survival in patients with this criteria averages around 70% In patients with cirrhosis and portal hypertension, 5-year survival decreases to around 25% Reference: Said A and Wells J. Minerva Medica. 2009; 100:51-68.

Liver Transplantation In patients with single nodules of less than 5 cm or up to 3 nodules no bigger than 3 cm (Milan Criteria) liver transplantation has shown 5 year survival of 71-74% Because the Milan Criteria includes a limited number of patients, authors have recently validated transplantation criteria (UCSF) that include patients with slightly more progressive disease Reference: Said A and Wells J. Minerva Medica. 2009; 100:51-68.

Liver Targeted Therapies RFA –by surgeons and interventional radiologists (IR) Drug-eluting beads embolization by IR Y90 chemoembolization by IR and Radiation Oncologist Cyberknife treatment or other form of radiation by Radiation Oncologist

Locoregional Therapy: PEI and RFA RFA, which delivers thermal energy to lesions causing necrosis, is generally used in patients with adequate hepatic reserve (Child-Pugh A/B) and tumors <3 cm1 3 year survival rates for RFA can range from ~63-81%2 PEI, in which 95% ethanol is injected to cause coagulative necrosis, is often used in patients with nodules <2-3 cm, who are not candidates for RFA due to tumor location1 3 year survival rates for PEI can range from ~48-67%2 References: Said A and Wells J. Minerva Medica. 2009;100:51-68. Cho, YK. Hepatology. 2009;49:453-459.

Locoregional Therapy: Y-90 Y-90 radioembolization is a form of intra-arterial brachytherapy in which particles of glass or resin are impregnated with the isotope yttrium-90 (90Y) and infused directly into the hepatic arteries via a catheter. Two products are currently available: TheraSphere® (MDS Nordion, Ottawa, Canada) and SIR-Spheres® (Sirtex Medical Ltd., Lane Cove, Australia)1 Patients eligible for Y-90 generally are ECOG 0-2, with good organ function, have tumor volume less than 70% of total liver volume, and no infiltrative disease or main portal vein thrombosis1 Median survival for HCC patients on SIR-Sphere can range from 7- 9.4 months2-3 Median survival for HCC patients on TheraSphere can range from 4.4 – 21.3 months4-6 References: Lewandowski RJ, et al. Cardiovasc Intervent Radiol. 2007;30:571-592 Lau WY, et al. Int J Radiat Oncol Biol Phys. 1998;40:583-592 Sangro B, et al. Int J Radiat Oncol Biol Phys. 2006;66:792-800 Kulik LM et al. Hepatology. 2008;47:71-817 Carr BI, et al. Liver Transpl. 2004;10(2 Suppl 1):S107-110 Geschwind JFH, et al. Gastroenterology. 2004;127(5 Suppl 1):S194-205

Locoregional Therapy: TACE TACE is selective arterial ablative therapy that interrupts blood supply via the injection of chemotherapeutic agents. It can be used to treat unresectable HCC tumors that are larger than 3 cm, and that cannot be well addressed by RFA1 Two key trials reported 1 year survival rates for TACE in the range of ~57-82%2-3 References: Said A and Wells J. Minerva Medica. 2009; 100:51-68. Lo CM, et al. Hepatology. 2002;35:1164-1171 Llovet JM, et al. Lancet. 2002;359:1734-1739.

Targeted Therapies Sorafenib Sharp trial: 602 Child’s A patients randomized to sorafenib vs placebo Median survival 10.7 months vs 7.9 months, HR 0.69, p< 0.001 -- Asian Trial 226 Child’s A patients Median Survival 6.2 months vs 4.1 months, HR 0.67, p=0.0155 Median PFS=2.8 vs 1.4months, p=0.009 Toh, et al., ASCO 2009, Llovet, et al., NEJM 359: 378, 2009

Phase 3 SHARP Trial: Adverse Reactions Sorafanib Phase 3 SHARP Trial: Adverse Reactions The most common Grade 3 adverse reactions included: Fatigue (9% Nexavar, 12% placebo) Diarrhea (10% Nexavar, 2% placebo) HFSR (8% Nexavar, <1% placebo) Abdominal pain (9% Nexavar, 5% placebo) The most common Grade 4 adverse reactions included: Fatigue (1% Nexavar, 2% placebo) Liver dysfunction (1% Nexavar, 1% placebo) Abdominal pain (0% Nexavar, 1% placebo) Reference: Nexavar [package insert]. Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ; Onyx Pharmaceuticals, Emeryville, CA; 2009.

Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C. Lancet Oncol. 2013 Jan;14(1):55-63. doi: 10.1016/S1470-2045(12)70490-4. Epub 2012 Nov 20.

Primary Endpoint: TTP (ITT Population) Median TTP Patients Events Tivantinib 6.9 wks 71 46 Placebo 6.0 wks 36 30 HR: 0.64 (90% CI: 0.43-0.94) Log Rank: P=0.04 Study powered to detect a treatment difference with a 1-sided type I error α = 0.05 PFS consistent with TTP: HR 0.67 (95% CI: 0.44-1.04) Log Rank: P=0.06 1 PR was observed in the 240mg BID group. Disease control rate: 44% on tivantinib (32-56) vs 31% (16-48) Of 23 crossed-over patients, 11 showed best response of SD (3 ongoing at time of data cut-off), 8 PD, 4 non evaluable ARQ 197-215 PRESENTED BY: LORENZA RIMASSA 20

Improved TTP in MET Diagnostic High Group Median TTP Patients Events Tivantinib 11.7 wks 22 14 Placebo 6.1 wks 15 13 HR: 0.43 (95% CI: 0.19-0.97) Log Rank: P=0.03 PFS: HR 0.45 (95% CI: 0.21-0.95) Log Rank: P=0.02 DCR: 50% on tivantinib (28-72) vs 20% (4-48) ARQ 197-215 PRESENTED BY: LORENZA RIMASSA

Improved OS in MET Diagnostic High Group Median OS Patients Events Tivantinib 7.2 mos 22 17 Placebo* 3.8 mos 15 HR: 0.38 (95% CI: 0.18-0.81) Log Rank: P=0.01 *8 MET Dx High patients crossed-over, 5 remained on open-label tivantinib for at least 6 weeks (1 non-evaluable at cut-off date) ARQ 197-215 PRESENTED BY: LORENZA RIMASSA

Tivantinib Results First, cMet expression was prognostic OS 9 months for cMet low and 3.8 months for cMet high (based on 28 patients) While tivantinib had no apparent effect in cMet low patients, cMet high patients appeared to get benefit

Systemic Therapy for HCC Sorafenib Clinical trials Lines of therapy Name of treatment Mechanism biomarker 1st Line (phase II), Sorafenib + LY2157299 VEGFR1-3, FGFR1-4, RET, KIT and PDGFR&bgr 2nd Line (phase III) NCT02029157 Tivantinib c-MET inhibitor; High c-met level 2nd Line (phase III) NCT01774344 Regorafenib inhibits multiple kinases

HCC Conclusions Sorafenib is the only FDA approved treatment for patient with advanced HCC and good liver function.

Management of bile duct cancer and gallbladder cancer

Challenges Difficulties with treating biliary tract and gallbladder cancers Heterogeneous disease Uncommon tumor Don’t even know the incidence since intrahepatic cholangiocarcinomas and HCC are lumped together in annual statistics Multiple locations: Intraheptaic, extrahepatic (bile ducts, Klatzkin, periampullary), gallbladder, We can’t be sure that these locations are truly the same pathology There are mixed tumor types (cholangiocellular)

Gem/Cis ABC-02 410 patients Metastatic disease (75%): locally advanced (25%) Gallbladder (36%) Bile duct 59% Ampulla (5%) Gemcitabine 1000mg/m2 day 1,8,15 of 28 d cycle + cisplatin 25mg/m2 day 1, 8 of 28 d cycle Valle, et al., ASCO 2009

Gem/Cis Grade 3-4 toxicity at 12 weeks PFS (p=0.003) Median Survival Hazard Ratio 0.68 Gemcitabine 57% 6.5 months 8.3 months Gemcitabine + cisplatin 8.5 months 11.7 months

Systemic Therapy Conclusions Chemotherapy is the standard for biliary tract cancers. The level 1 evidence standard is gemcitabine and cisplatin chemotherapy Other combination regimens have activity The future of this disease should lie in targeted therapies and there are a lot of targets These should be applied wisely However, these are rare tumors and subdividing them by biomarkers may prove difficult

Systemic Therapy for Cholangiocarcinoma Cisplatin + Gemcitabine 5-FU containing chemotherapy Clinical trial: Cisplatin + c-met inhibitor Tumor molecular profile

Summary Surveillance for early diagnosis and treatment is the key to improve outcome. For a patient with a newly diagnosed liver cancer, a multidisciplinary team should be involved in developing the treatment plan. Molecular profiling important for the future