1. Pancreatic Cancer: Are We Moving Forward Yet? Muhammad Wasif Saif Yale University School of Medicine. New Haven, CT, USA Highlights from the Gastrointestinal Cancers Symposium. a Orlando, FL, USA. January 20 th , 2007 a The Gastrointestinal Cancer Symposium was jointly sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Gastroenterological Association Institute (AGAI), and the Society of Surgical Oncology (SSO)

7. CALGB 80303: Demographic Features 602 patients are currently valuable Gemcitabine + placebo (n=300) Gemcitabine + bevacizumab (n=302) 84% 85% Stage IV 11% 11% Prior radiation therapy 9% 9% ECOG performance status 2 65.0 63.8 Median age (years) 51% / 49% 58% / 42% Male/female ratio

8. CALGB 80303: Efficacy 33.6% 40.9% Stable disease 10.3% 13.5% Overall response rate 4.3 months (95% CI: 3.8-5.5) 4.8 months (95% CI: 4.2-5.3) Median progression free survival 6.0 months (95% CI: 4.8-6.9) 5.7 months (95% CI: 4.8-5.9) Median overall survival Gemcitabine + placebo (n=300) Gemcitabine + bevacizumab (n=302)

9. CALGB 80303: Hematological Toxicity 518 patients are currently valuable for toxicity 11% 12% Thrombocytopenia 8% 5% Anemia 29% 31% Neutropenia Gemcitabine + placebo (n=254) Gemcitabine + bevacizumab (n=264)

10. CALGB 80303: Toxicity 518 patients are currently valuable for toxicity 2% 8% Hypertension 0% 0% Perforation 2% 3% Gastrointestinal bleed 2% 1% Cardiovascular accident 1% 2% Proteinuria 9% 9% Venous thrombosis Gemcitabine + placebo (n=254) Gemcitabine + bevacizumab (n=264)

16. GEMOXCET: Efficacy Results 64 patients are currently evaluable 54% (95% CI: 37-78%) 6-month survival 155 days Median time to progression 24% Stable disease 12 patients (18.8%) Partial response 1 patient ( 1.6% ) Complete response 38% Overall response rate Results Efficacy parameters

22. Sorafenib plus Gemcitabine: Efficacy Results 17 patients are currently valuable 23% 6-month survival 3.2 months Median progression free survival 4 months Median overall survival 23% Stable disease 0 Response rate

23. Sorafenib plus Gemcitabine: Toxicity Frequency of grade 3-4 toxicities 6% Gastrointestinal bleeding 6% Diarrhea 6% Hand-foot syndrome 6% Hypertension 12% Nausea 12% Rash 18% Fatigue 18% Thrombosis 6% Thrombocytopenia 29% Neutropenia

34. The Mayo Clinic Experience: Results (I) CT: chemotherapy CT-RT: concurrent chemo-radiotherapy 1.6 9 Adjuvant CT only 1.4 28 Adjuvant CT-RT + CT 1.2 246 Adjuvant radiotherapy 1.0 180 No adjuvant radiotherapy Mean no. of adverse prognostic factors No. of cases Treatment

35. The Mayo Clinic Experience: Results (II) - Overall survival - CT: chemotherapy CT-RT: concurrent chemo-radiotherapy 0 15% 1.1 (0.4-1.8) Adjuvant CT only 34% 61% 2.9 (1.4-6.9) Adjuvant CT-RT + CT 28% 50% 2.1 (1.6-2.6) Adjuvant radiotherapy 17% 39% 1.6 (1.2-1.8) No adjuvant radiotherapy 5 years 2 years Median (95% CI) years Treatment

38. Prediction of Survival Following Pancreatic Cancer Surgery by Lymph Node Ratio

43. Genexol-PM ® : Objectives 1.Maximizing the administrable amount of paclitaxel 2. Minimizing the systemic toxicity related to vehicle Lower Toxicity Better Efficacy

45. Genexol-PM ® : Efficacy Parameters a ITT: intent-to-treat b EE: efficacy evaluable EE b ITT a EE b ITT a 3 (8.1%) 3 (6.7%) 0 0 CR+PR 11 (29.7%) 23 (62.1%) 2 (5.4%) 1 (2.7%) (n=37) 3 (60.0%) 2 (40.0%) 0 0 (n=5) 11 (24.4%) 3 (27.3%) Progressive disease 23 (51.1%) 2 (18.2%) Stable disease 2 (4.4%) 0 Partial response (PR) 1 (2.2%) 0 Complete response (CR) (n=45) (n=11) 300 or 350 435 Dose level (mg/m 2 )

46. Genexol-PM ® : Toxicity NA: not applicable NA 23 (41.1%) NA 23 (51.1%) NA 0 Alopecia a 9 (16.1%) 30 (53.6%) 6 (13.3%) 26 (57.8%) 3 (27.3%) 4 (36.4%) Neuropathy 0 11 (19.6%) 0 11 (24.4%) 0 0 Dysgeusia 0 11 (19.6%) 0 10 (22.2%) 0 1 (9.1%) Arthralgia ≥ grade 3 Any ≥ grade 3 Any ≥ grade 3 Any 4 (7.1%) 8 (14.3%) 2 (3.6%) 3 (5.4%) 2 (3.6%) 19 (33.9%) 4 (8.9%) 8 (17.8%) 2 (4.4%) 2 (4.4%) 2 (4.4%) 14 (31.1%) 0 0 0 1 (9.1%) 0 5 (45.5%) 13 (23.2%) 21 (37.5%) 23 (41.1%) 23 (41.1%) 17 (30.4%) 24 (42.9%) (n=56) Overall 17 (37.8%) 6 (54.5%) Vomiting 17 (37.8%) 6 (54.5%) Nausea 12 (26.7%) 1(9.1%) Hypersensitivity 18 (40.0%) 6 (54.5%) Neutropenia 20 (44.4%) 1(9.1%) Fatigue 16 (35.6%) 1(9.1%) Diarrhea 300 or 350 (n=45) 435 (n=11) Dose level (mg/m 2 )

49. S-1: An Oral Fluoropyrimidine A phase I study revealed that the combination of gemcitabine and S-1 appears to be feasible and effective against advanced pancreatic cancer [13] [13] Ueno H, et al. Oncology 2005; 69:421-7. [Link] Catabolism Anabolism Oxo O O H COOK N HN N Oxo 1 O O H COOK N HN N CDHP OH HO Cl N CDHP 0.4 OH HO Cl N DPD CDHP F - β - Ala Hand - Foot Syn. Neuro toxicity Cardio toxicity Liver and Tumor (CYP 2A6) 5 - FU Oxo GI tract FdUMP GI toxicity (Diarrhea, Stomatitis) 1 Tegafur Tumor FdUMP Antitumor activity Bone marrow FdUMP Myelo toxicity OPRT O O F O N HN O O F O N HN

51. Gemcitabine plus S-1: Efficacy 55 patients are currently valuable 33% 1-year survival rate 10.1 months Median overall survival 5.9 months Median progression-free survival 48% Stable disease 44% Overall response rate 44% Partial response

52. Gemcitabine plus S-1: Toxicity a only one episode of infection with grade 3-4 neutropenia - Frequencies of grade 3-4 toxicities - 6% Fatigue 6% Nausea 7% Rash 17% Anorexia 22% Thrombocytopenia 80% a Neutropenia

54. What We Miss?