1. Highlights 2007: Non-colorectal GI cancer Alan P. Venook, M.D. University of California, San Francisco

2. Highlights: non-colorectal GI Pancreas cancer  Phase III trials Gastric cancer  Genetic risk Esophageal / GE junction / gastric  Prediction of outcome  Preoperative therapies  S-1

3. Highlights: non-colorectal GI Pancreas cancer  Phase III trials Gastric cancer  Genetic risk Esophageal / GE junction / gastric  Prediction of outcome  Preoperative therapies  S-1

4. Highlights: non-colorectal GI Pancreas cancer  Gemcitabine +/- cetuximab  Gemcitabine +/- bevacizumab

5. Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Locally Advanced or Metastatic Pancreatic Adenocarcinoma Southwest Oncology Group Protocol S0205 PA Philip, J Benedetti, C Fenoglio-Preiser, M Zalupski, H Lenz, E O’Reilly, R Wong, J Atkins, J Abbruzzese, C Blanke On behalf of SWOG, CALGB, NCIC, and the CTSU

6. S0205 Study Schema Stratify Locally advanced versus metastatic Prior pancreatectomy Yes versus No Performance status 0/1 versus 2 Gemcitabine + Cetuximab Gemcitabine + Cetuximab Gemcitabine RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE

7. 5.9 6.4 S0205: Primary Endpoint Survival in All Patients HR = 1.09 (95% CI: 0.93, 1.27)

8. 3.0 3.5 S0205: Progression-Free Survival in All Patients HR = 1.13 (95% CI: 0.97, 1.31)

9. S0205: Objective Tumor Response ResponseGem + Cetux (%) N = 316 Gem (%) N = 326 CR01 PR1213 SD3830 CR + PR + SD5044 PD4047

10. A double-blind, placebo-controlled randomized Phase III trial of Gemcitabine plus Bevacizumab versus Gemcitabine plus placebo in Patients with Advanced Pancreatic Cancer: A preliminary analysis of Cancer and Leukemia Group B H.L. Kindler, D. Niedzwiecki, D. Hollis, E. Oraefo, D. Schrag, H. Hurwitz, H.L. McLeod, M.F. Mulcahy, R. L. Schilsky, R. M. Goldberg

11. CALGB: Gemcitabine +/- bevacizumab Kindler, et al…  Median OS: 5.7 v. 6.0 months  Median failure-free survival: 4.8 v. 4.3 months  RR: 13% v. 11%  Stopped and unblinded at interim analysis due to futility

12. Lowlights: pancreas cancer Overall survival Gemcitabine +/- cetuximab: 6.4 v. 5.9 mo Gemcitabine +/- bevacizumab: 5.7 v. 6.0 mo

13. Lowlights: pancreas cancer Overall survival Gemcitabine +/- cetuximab: 6.4 v. 5.9 mo Gemcitabine +/- bevacizumab: 5.7 v. 6.0 mo Gemcitabine +/- erlotinib: 6.24 v. 5.91 mo*  Moore et al, JCO, 2007 The standard is unsatisfactory and new drugs and study designs are needed * Statistically significant

14. Highlights: non-colorectal GI Pancreas cancer  Phase III trials Gastric cancer  Genetic risk Esophageal / GE junction / gastric  Prediction of outcome  Preoperative therapies  S-1

15. Hereditary Diffuse Gastric Cancer: Natural History, Pathology, Screening Limitations, and Prophylactic Total Gastrectomy in CDH1 Mutation Carriers by Henry Lynch*, Carlos Caldas, Debrah Wirtzfeld, Carlos Vaccaro, Wendy Rubinstein, Scott Weissman, Pardeep Kaurah, Niki Boyd, Rebecca Fitzgerald, David Huntsman

16. Loss of E-cad is a defining feature of both DGC and lobular breast cancer  -catenin binding site

17. Criteria for CDH1 mutation testing modified to reflect current data 1.Family with two or more cases of GC, with at least 1 DGC diagnosed before the age of 50. (>40%)* 2.3 or more first/second-degree relatives with confirmed diffuse gastric cancer, irrespective of age. 3.Isolated individual diagnosed with DGC at less than 35 years from a low incidence population (>10%)* 4.Isolated personal history of both DGC and LBC (unknown)* 5.Family with multiple LBC with or without DGC in first or second degree relatives (unknown)* * Percentage mutation pick up rate from low incident populations Modified from Caldas et al. J Med Genet, 1999 and Suriano et al. Clin Can Res, 2005

18. Currently 31/39 (80%) of prophylactic gastrectomies reviewed in total had occult DGC’s All cancers were very superficial, the rate of progression of these lesions and the the secondary mutations required for invasion of the muscularis propria are unknown 44-60% <1% 26-43% 3% 50-80% 28-33% F Carneiro, D Huntsman et al J Pathol 2004; 203: 681–687

19. Highlights: non-colorectal GI Pancreas cancer  Phase III trials Gastric cancer  Genetic risk Esophageal / GE junction / gastric  Prediction of outcome  Preoperative therapies  S-1

20. M. A. Shah, H. Yeung, D. Coit, R. Trocola, D. Ilson, J. Randazzo, L. Tang, M. Brennan, C. Divgi, D. P. Kelsen A phase II study of preoperative chemotherapy with irinotecan and cisplatin for gastric cancer: FDG- PET/CT predicts patient outcome

21. FDG-PET/CT predicts outcome in gastric ca Shah, et al…  N = 42 locally advanced disease  31/42 PET avid  Neoadjuvant irinotecan / cisplatin  SUV drop from baseline to d35 correlates with path response, but d15 does not  Cut-off of 45% decrease d35 SUV:  DFS >23 months v. 14.4 months

22. S. Rao, D. Cunningham, M. Benson, R. Te Poele, L. Welsh, N. Starling, A. Norman, C. Saffrey, P. Workman, P. Clarke A prospective study to evaluate the role of gene expression profiles in predicting clinical outcome of patients receiving preoperative chemoradiotherapy for oesophagogastric cancer

23. Gene expression predicts outcome in gastric ca Rao, et al…  Neoadjuvant chemotherapy  N = 35 (esophagus, 23; GE junction, 12)  Two distinct gene clusters:  N = 17 poor prognosis -- 2 yr survival = 17%  N = 18 good prognosis -- 2 yr survival = 55%  Affected pathways: tyrosine kinase signaling and cell growth

24. V. Boige, J. Pignon, B. Saint-Aubert, P. Lasser, T. Conroy, O. Bouche, P. Segol, L. Bedenne, P. Rougier, M. Ychou Final results of a randomized trial comparing pre- operative 5-FU / cisplatin to surgery alone in adenocarcinoma of stomach and lower esophagus: FNLCC ACCORDO7-FFCD 9703 trial

25. Neoadjuvant therapy v. surgery alone Boige, et al…  Neoadjuvant 5-FU/cisplatin; resectable gastric or GE junction  N = 224 (accrued over 8 years)  R0 resection: 73% v. 84% favoring combined rx  5 yr DFS: 21% v. 34%  OS: 24% v. 38%  Neoadjuvant 5-FU/cisplatin improves outcomes

26. Michael Stahl on behalf of the German Oesophageal Cancer Study Group PreOperative Chemotherapy or Radiochemotherapy in Esophago-gastric Adenocarcinoma Trial POET

27. Treatment Arm A Week Arm B PLF 2 x 6 weeks PLF, 3 weeks 15 x 2 Gy, 3 weeks PE, 1 week Surgery 1 131721 P: Cisplatin E: Etoposide LF: Leukovorin / 5-FU

28. Logrank p = 0.07 HR Arm B vs. A 0.67 (0.41-1.07) Arm B Arm A OS: Follow-up 45.6 mo 47.4% 27.7%

29. Individual patient data-based meta- analysis assessing the interest of pre- operative chemotherapy in resectable oesophageal carcinoma Abstract: 4512 Thirion P., Michiels S., Le Maître A., Tierney J. The Meta ‑ Analysis of Chemotherapy in Esophagus Cancer Collaborative Group

30. Materials 12 eligible trials identified - 2,290 patients 9 available trials (10 comparisons) - 2,102 patients (92%) Median follow up across trials: 5.3 years (range: 4.9 - 6.0)

31. Primary End-point: Overall Survival

32. Sub-group Analyses The overall survival and disease-free survival benefit of the addition of pre-operative chemotherapy was seen across:  Age (50 60)  Gender  Initial PS  Histological Type Adenocarcinoma282/385315/392-29.5148.4 Squamous cell450/564471/563-15.0226.7 Category Chemo preop No. Events / No. Entered Control O-EVarHazard ratioHR [95% CI] Test for interaction:p = 0.21 Chemo preop better|Control better 0.00.51.01.52.0

33. Esophagus / GE junction conclusions  Data supports the roles of chemotherapy and radiation in the management of resectable cancers  Surgery as a single modality is probably suboptimal

34. F-  -Ala Neurotoxicity GI toxicity Myelotoxicity 5-FU Anti-tumoractivity S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7 DPD Tegafur OPRT

35. F-  -Ala Neurotoxicity GI toxicity Myelotoxicity 5-FU Anti-tumoractivity S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7 DPD Tegafur CDHP OPRT Oxo inhibit inhibit

36. F-  -Ala Neurotoxicity GI toxicity Myelotoxicity 5-FU Anti-tumoractivity S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7 DPD Tegafur CDHP OPRT Oxo inhibit inhibit

37. N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)

38. S-1 40 mg/m 2, po, bid, days 1-28 q 6 weeks Stratified by (minimization) ・ Institution ・ PS 0/1/2 ・ Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx 5- FUci CPT-11 + CDDP S-1 Randomization 800 mg/m 2, continuous inf, days 1-5 q 4 weeks CPT-11 70 mg/m 2, div, days 1&15 CDDP 80 mg/m 2, div, day 1 q 4 weeks Continued until disease progression, unacceptable toxicities, patient’s refusal BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/day

39. 0.001 0.62-0.900.75 4.2M 234 <0.001 - 0.57-0.83 - 95%C.I. - 2.9M 234 0.69 4.8M 236 HR Median n P-value † 1224 (months) 0 50 (%) 100 Response rate S-1 5-FUci CPT-11+CDDP 5-FUci CPT-11 +CDDPS-1 CR+PR 156849 n 175181175 RR9%38%28% PFS

40. Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment of advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment of stomach cancer H. Narahara 1, W. Koizumi 2, T. Hara 3, A. Takagane 4, T. Akiya 5, M. Takagi 6, K. Miyashita 7, T. Nishizaki 8, O. Kobayashi 9, S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;

41. AGC No prior Chemo. R S-1 alone S-1: 40-60 mg BID for 28 days q6wks S-1 + CDDP S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m 2 iv on day 8 Central Randomization (dynamic balancing) (dynamic balancing) Adjustment Factors: Institute PS PS Unresectable vs Recurrent Unresectable vs Recurrent

42. Months Estimated probability (%) 11.013.0S-1S-1+CDDP No. of pts 150148 MST11.013.0 1 yr survival 46.7 % 54.1 % 2 yr survival 15.3 % 23.6 % Log-rank p-value: 0.0366 HR: 0.774 [ 95% CI: 0.608 – 0.985] Median follow-up time (M): 34.6

43. No. Response Overall RR CRPRSDPDNE S-110613234345 31 % S-1+CDDP8714613243 54 %  Criteria : RECIST (Extramural Review) Fisher’s Exact Test p-value: 0.0018

44. Highlights: non-colorectal GI Pancreas cancer  Phase III trials Gastric cancer  Genetic risk Esophageal / GE junction / gastric  Prediction of outcome  Preoperative therapies  S-1

45. Highlights: non-colorectal GI Pancreas cancer  Phase III trials Gastric cancer  Genetic risk Esophageal / GE junction / gastric Hepatocellular carcinoma  Sorafenib