1. TARA SEERY, MD

3. Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type The vast majority of patients are inoperable at the time of diagnosis Pancreatic cancer is inherently resistant to most currently available therapies Many patients suffer from rapidly declining performance status Compared with other cancer types, research funding for pancreatic cancer is disproportionately low given its mortality rate (fourth for cancer-related deaths in the US population)

4. Incidence = mortality

5. Ryan DP et al. N Engl J Med 2014;371:1039-1049

6. BIOLOGIC FEATURES Very high rate of activating mutations in KRAS (>90%) Propensity for both local invasion and distant metastasis Extensive stromal reaction Hypovascular and hypoxic microenvironment Reprogramming of cellular metabolism Evasion of tumor immunity

7. Pancreatic cancer: epidemiology Incidence of 10 per 100,000 80% ductal adenocarcinoma 10% other exocrine tissue– Acinar cell, cyst adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN) 10% neuroendocrine KKrejs GJ. Dig Dis. 2010; 28:355-358

8. Diagnostic tools for pancreatic cancer Lab studies – Tumor markers i.e.CA19-9 – Glucose intolerance Imaging modalities – CT scan – EUS – ERCP – MRI/MRCP – PET scanning – Staging laparoscopy

9. Major clinical stages Resectable -- Locally advanced -- Metastatic TNM Staging Stage 1 T1 (≤ 2cm) N0 M0 T2 (≥ 2cm) N0 M0 Stage 2 T3 (beyond the pancreas but with out involvement of celiac axis or SMA) N0 M0 T1/2 N1 (regional LN) M0 Stage 3 T4 (involves celiac axis or SMA) Nx M0 Stage 4 M1

10. Metastasis, M0 vs M1

11. T1 ( 2cm)

12. T3 (Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery) vs T4 (Tumor involves the celiac axis or superior mesenteric artery (unresectable primary tumor))

13. N0 (No regional lymph node metastasis) vs N1 (Regional lymph node metastasis)

14. Ryan DP et al. N Engl J Med 2014;371:1039-1049

15. Overall survival For all stages combined, the 1-year relative survival rate is 25%, and the 5 year survival is less than 5% For Local Disease – 5 year survival is approx 20% For Locally Advanced and for Metastatic Disease the median survival is 10 and 6 months with treatment Untreated metastatic has a median survival of 3-5 months

16. Stage 1 and 2 Radical pancreatic resection: Whipple procedure (pancreaticoduodenal resection) Total pancreatectomy when necessary for adequate margins Distal pancreatectomy for tumors of the body and tail of the pancreas Radical pancreatic resection with: Postoperative chemotherapy (gemcitabine or 5FU) Postoperative chemotherapy and radiation therapy

17. Whipple procedure

18. Ryan DP et al. N Engl J Med 2014;371:1039-1049

19. Treatment options under clinical evaluation Gemcitabine and capecitabine (ESPAC-4) Gemcitabine and erlotinib (CONKO-005) Gemcitabine with or without 5FU chemoradiation (RTOG 0848) Gemcitabine vs Gemcitabine/Abraxane Preoperative chemotherapy (ACOSOG) -- FOLFIRINOX Preoperative chemotherapy and radiation therapy

20. Stage III Technically unresectable because of local vessel impingement or invasion by tumor Benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological Stage III and stage IV pancreatic cancer are both incurable, the natural history of stage III (locally advanced) disease may be different than it is for stage IV disease 30% of patients presenting with stage III disease died without evidence of distant metastases

21. Treatments Palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement Chemotherapy with gemcitabine, gemcitabine and erlotinib or abraxane, or FOLFIRINOX Chemoradiation (for obstructions) followed by chemotherapy Chemotherapy followed by chemoradiation for patients without metastatic disease --- now LAP07 trial worse with XRT

22. Ryan DP et al. N Engl J Med 2014;371:1039-1049

24. 600,000 to 1,000,000 cases diagnosed worldwide every year 5 th most common cancer worldwide 2 nd leading cause of cancer-related death worldwide Incidence and yearly deaths essentially the same Men > Women 50% of cases & deaths thought to occur in China alone Increasing incidence in “Western” countries Hepatitis C viral infection Obesity Epidemic Rates per 100,000

25. Liver Cancer Incidence: Males Rate Per 100,000 International Agency for Research on Cancer. GLOBOCAN 2002. Available at: http://www-dep.iarc.fr. Accessed May 5, 2008.

27. More than 80% of HCC is associated with chronic liver disease HBV infection is most common in Asia & Africa 380,000,000 cases HBV worldwide More than 8% of the population in these regions have chronic HBV infection 100x increase in risk of developing HCC vs. non-carrier Up to 40% who develop HCC are non-cirrhotic Responsible for 60% of HCC in developing countries, and 23% of HCC in developed countries HCV infection/cirrhosis in Western countries & Japan 170,000,000 cases worldwide Responsible for 33% of HCC in developing countries, and 20% of HCC in developed countries Alcoholic cirrhosis Non-Alcoholic Steatohepatitis (NASH)

28. Doubling time for HCC tumors is 2 to 3 months Normal life expectancy for HCC (Child-Pugh A) is 8 to 12 months from diagnosis Mean survival for symptomatic patients with HCC is 2 to 3 months 5-year survival (all patients – U.S.) is 26%

29. Surgical Resection Hemihepatectomy Segmentectomy Non Anatomic wedge resection Orthotopic Liver Transplantation For selected cases of hepatoma, hepatoblastoma, neuoroendocrine tumors Radiofrequency ablation Microwave ablation Chemoembolization Radioembolization Systemic chemotherapy Irreversible electroporation

31. European Association for the Study of the Liver; J. Hepatol. 56, 908–943 (2012).

32. Ablation (RFA, cryoablation, percutaneous ETOH, microwave) All tumors amendable Thermal ablation need a margin of normal tissue Accessible tumors by percutaneous, laparoscopic or open Caution with ablation near major vessels, major bile ducts, diaphragm, and intra-abdominal organs Curative in tumors ≤3 cm Tumors 3-5 cm may be treated to prolong survival using arterial directed therapies or with combination of an arterially directed therapy and ablation ≥5cm tumors use arterially directed therapies

33. Arterially directed therapies All tumors amenable provided that the arterial blood supply to the tumor may be isolated without excessive non-target treatment TAE (transarterial bland embolization), TACE (chemoembolization), TACE with drug eluting beads, Y90 Contraindicated if bili >3 Y90 contraindicated if bili>2 Contraindicated if main portal vein thrombosis and CP class C

34. Potential Severe Adverse Events from Chemoembolization Hepatic insufficiency or infarction Abscess Hepatic failure Biliary necrosis Tumor rupture Non targeted embolisation of gall bladder, stomach, small bowel

35. Systemic Therapy –Historically ineffective Hormonal agents – Tamoxifen Chemotherapeutic agents –Doxorubicin – 16% response rate, no improved survival –PIAF (cisplatin, Ifn-α, doxorubicin, 5-FU) – 26% partial response rate, no improved survival Octreotide Thalidomide –Sorafenib and the SHARP Trial Multikinase inhibitor –Blocks cell proliferation (Raf/MEK/ERK pathway) –Blocks angiogenesis (VEGFR-2, VEGFR-3, PDGFR-β) HCC Management – Systemic Therapy

36. Molecular Signalling Pathways in HCC Wilhelm S, et al. Cancer Res. 2004;64:7099-7109. Autocrine loop Tumor Blood Vessels Tumor Cell Growth and survival factors (eg, VEGF, PDGF) Sorafenib PDGF VEGF EGF/HGF Proliferation Survival Mitochondria EGF/HGF HIF-2 Nucleus Apoptosis ERK RAS MEK RAF

37. Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Eng J Med 2008; 359(4):378-90. Phase III SHARP Trial Study Design Multi-center, Phase III study Inclusion criteria Histology proven HCC Advanced, unresectable HCC At least one measurable untreated lesion ECOG ≤ 2 Child-Pugh class A No prior systemic treatment Randomization Double-blind placebo controlled trial (1:1) Accrual: March 2005-April 2006

38. Sorafenib in Advanced HCC (SHARP): Survival Survival Probability Mos Since Randomization 1.00 0 0.75 0.50 0.25 Sorafenib median OS: 46.3 wks (10.7 mos) (95% CI: 40.9-57.9) Placebo median OS: 34.4 wks (7.9 mos) (95% CI: 29.4-39.4) HR (S/P): 0.69 (95% CI: 0.55-0.87; P <.001 ) Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390. 01234568910111213141516717

39. Sorafenib vs Placebo in Advanced HCC (SHARP): Response Time to symptom progression (FSHI8-TSP scoring): no significant differences between treatment groups (P =.77) *RECIST criteria, independent review. Result Sorafenib (n = 299) Placebo (n = 303) Overall response,* n (%)  CR 0 (0)  PR 7 (2.3)2 (0.7) SD, n (%) 211 (71)204 (67) PD, n (%)54 (18)73 (24) PFS rate at Month 4, %6242 Median treatment duration, wks2117 Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.

40. Unmet Needs in Advanced HCC First-line therapies that improve clinical outcomes compared with treatment with sorafenib (the standard of care) [1,2] with regarding Efficacy [1] Safety and tolerability [1] Options also needed for patients who are ineligible Quality of life [3] Second-line therapies for patients who progress on or do not tolerate sorafenib [1] Ongoing phase III trials are addressing unmet needs in first-line and second-line therapy for advanced HCC 1. Finn RS. Clin Cancer Res. 2010;16:390-397. 2. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. 3. Fan SY, et al. Clin Gastroenterol Hepatol. 2010;8:559-564.

41. Tivantinib – MET inhibitor A non-ATP-competitive inhibitor of c-Met, which has been implicated in cancer cell proliferation, migration, invasion, and metastasis The c-Met receptor tyrosine kinase is the only known high- affinity receptor for hepatocyte growth factor Binding of HGF to the c-Met extracellular ligand-binding domain results in receptor multimerization and phosphorylation of multiple tyrosine residues in the intracellular portion of c-Met

43. Summary HCC is the 3 rd most common cause of cancer death worldwide with increasing incidence in the U.S. HCC is a biologically heterogeneous tumor type due to longstanding hepatocyte regeneration and accumulated mutations from premalignant liver injury state Sorafenib remains the only proven agent with survival benefit with advanced HCC but novel agents are on the horizon