1. Upper Gastrointestinal Overview 2007- 2008: Practical Implications of the Newest Data Esophageal and Gastric Cancers Johanna Bendell, MD Sarah Cannon Research Institute

2. Conflict of Interest Disclosure Consultant or Advisory Role –Amgen –Array Pharmaceuticals –Genentech –Roche Honoraria –Amgen –Roche –Genentech –Array Pharmaceuticals Research Funding –Bristol-Myers Squibb –Genentech –Roche –Sanofi-Aventis –Novartis

3. Esophageal Cancer 16,470 new cases estimated for 2008 –14,280 estimated deaths Adenocarcinoma incidence rate increasing by 20% per year in U.S –EtOH, tobacco, obesity, genetics, diet –Barrett’s esophagus –Older trials have more patients with SCC –Adenocarcinomas predominate most trials now –Is there a difference? GE junctional cancers –Increase in distal esophageal and proximal gastric cancers –Is there a difference?

4. Localized disease Controversy –Surgery alone –Preoperative chemotherapy –Preoperative chemoradiation therapy –Chemoradiation therapy alone

5. Preoperative chemotherapy Study# Patients PathologyChemotherapyTumor Location 5-year survival MRC OEO-2, 2002 Chemo: 400 Surgery: 402 SCC, Adeno Cisplatin/5-FUStomach 10% Distal eso 65% Chemo: 23% Surgery: 17% P = 0.03 Cunningham et al, 2006 Chemo: 250 Surgery: 253 AdenoECFStomach 74% GE jn 12% Distal eso 14% Chemo: 36.3% Surgery: 23.0% P = 0.001 Kelsen et al, 2007 Chemo: 233 Surgery: 234 SCC, AdenoCisplatin/5-FUEsophagusChemo: 26% Surgery: 23% 3 year P = 0.53

6. FP (*) x 2/3 every 28 days Resection Within 4 weeks 4 - 6 weeks Resection 4 – 6 weeks FP x 3/4 or no treatment Follow-up Randomization CT + S S ACCORD 07-FFCD 9703 (*) FP = 5FU: 800 mg/m² CI x 5 days - CDDP: 100 mg/m² at d1 or d2, 1-hr infusion Boige, ASCO 2007

7. CT + S N = 113 Preop CT (2-3 cycles) N = 98 (89%) Surgery N = 109 (96%) Postop CT (1-4 cycles) N = 54 (51%) S N = 111 Surgery N = 110 (99%) Trial profile Boige, ASCO 2007

8. Disease-free survival 5-year DFS: 21% (14-30%) vs 34% (26-44%) 0-0.5 1 2 3 4 5 6 7 111 57 35 28 21 14 11 6 113 77 53 44 34 25 17 14 years At risk ___ S ___ CT + S Logrank p value = 0.0033 Hazard Ratio = 0.65 (95% CI 0.48-0.89) Boige, ASCO 2007

9. ___ S ___ CT + S years Overall survival At risk 5-year OS: 24% (16-33%) vs 38% (28-47%) Logrank p value = 0.021 Hazard Ratio = 0.69 (95% CI 0.50-0.95) Boige, ASCO 2007

10. ACCORD07-FFCD 9703 Preoperative chemotherapy 14% improvement in 5 year OS –Similar to MAGIC (13%) –MRC Preop ECF vs. CF Decrease in systemic recurrence –Local recurrence 26% (S) vs. 24% (CT+S) –Systemic recurrence 56% (S) vs. 42% (CT+S)

11. Preoperative Chemoradiation Study# PatientsPatholog y ChemotherapyRadiation (Gy) 3-year survival Walsh et al, 1996 Trimodality: 58 Surgery: 55 AdenoCisplatin/5-FU40Tri: 32% Surgery: 6% P = 0.01 Bosset et al (EORTC), 1997 Trimodality: 143 Surgery: 139 SCCCisplatin37Tri: 37% Surgery: 35% P = NS Urba et al, 2001 Trimodality: 50 Surgery: 50 SCC, Adeno Cisplatin/5- FU/vinblastin e 45Tri: 30% Surgery: 16% P = 0.15 Burmeister et al, 2005 Trimodality: 128 Surgery: 128 SCC, Adeno Cisplatin/5-FU35Tri: 33% Surgery: 30% P = 0.57 Tepper et al (CALGB), 2006 Trimodality: 30 Surgery: 26 SCC, Adeno Cisplatin/5-FU50.4Tri: 39% Surgery: 16% 5 year P < 0.008

12. POET Trial Arm A Week Arm B PLF IPLF III (3 weeks) 15 x 2 Gy in 3 weeks PE (1 week) Surgery 1 13141720-21 PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leucovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d 1,8,15,22,29,36 PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5 PLF II 6 7 PLF IPLF II Stahl, ASCO 2007

13. Overall Survival Logrank p = 0.07 HR Arm B vs. A 0.67 (0.41-1.07) Arm B Arm A Follow-up 45.6 mo 47.4% 27.7% Stahl, ASCO 2007

14. Freedom from Local Tumor Progression Logrank p = 0.06 HR Arm B vs. A 0.45 (0.19 -1.05) 76.5% 59.0% Arm B Arm A Stahl, ASCO 2007

15. Neoadjuvant vs. adjuvant approach Roth, et al. World GI 2007 Randomized 70 patients with locally advanced gastric cancer to 4 cycles of preoperative or adjuvant DCF Original plan to randomize 252 patients –Closed early due to poor accrual

16. TCF => S N = 34 Preop CT (4 cycles) Started N=33 (97%) Completed N= 25 (74%) Surgery N = 32 (94%) Postop CT (4 cycles) Started N = 23 (66%) Completed N = 12 (34%) S =>TCF N = 35 Surgery N = 35 (100%) SAKK Neoadjuvant vs. Adjuvant Trial pCR in 4 patients (12.9%) Roth, World GI 2007

17. What do we see in local treatment of esophageal cancer? Many of these trials are mixed populations –Adeno, SCC –Esophageal, GE junction, gastric cancers – accrual issues Surgery alone is not enough Preoperative chemotherapy improves survival for patients (now 3/4 trials, 1 meta-analysis) Preoperative chemoradiation therapy likely better than surgery alone, and maybe better than chemotherapy alone –Chemoradiation more toxic –True for squamous and adenos –Subgroup of patients who do not need surgery?

18. What do we do now? CRITICS Trial –Preoperative ECX, rand postop chemoradation or chemo alone Korean Trial –Preoperative cisplatin/capecitabine, then randomization to chemoradiation or chemo alone CALGB 80101 –Postoperative chemoradiation with 5-FU or ECF MRC OEO5 –Preoperative ECF vs. CF MAGIC 2 –Preoperative ECX with or without bevacizumab RTOG 0436 –Preoperative chemoradiation with or without cetuximab CALGB 80302 –PET as prognostic indicator

19. Metastatic Gastric Cancer Gastric cancer –21,500 new cases expected in the U.S. in 2008, 10, 880 deaths Unclear as to what is best metastatic regimen –ECF, DCF, IC, EOX? –Role of oral fluoropyrimidines Is combination therapy better than sequential?

20. S-1 Oral fluoropyrimidine consisting of tegafur, CDHP, and OXO in a 1:0.4:1 molar ratio –tegafur is converted to 5-FU –CDHP (chloro-2.4-dihydroxypyridine) inhibits DPD, preventing 5-FU degradation –OXO (potassium oxonate) protects against drug induced diarrhea caused by phosphorylation of 5- FU by inhibiting the responsible enzyme – OPRT (oronate phosphoribosyl transferase)

21. S-1 40 mg/m 2, po, bid, days 1-28 q 6 weeks 5-FU CI CPT-11 + CDDP S-1 Randomization 800 mg/m 2 /day, ci, 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 Phase III Study (JCOG9912) 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 Boku, ASCO 2007

22. Progression-free Survival and Response rate Response rate - in pts with target lesion - 5-FU CI CPT-11 +CDDPS-1 CR+PR156849 n175181175 RR9%38%28% CR and PR were confirmed by central review 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 †: one-sided log-rank test (superiority) S-1 5-FU CI CPT-11+CDDP PFS Boku, ASCO 2007

23. 122436 (months)0 50 (%) 100 Overall Survival P-value 0.034 † 0.055 † - 0.68-1.01 0.70-1.04 - 95%C.I. -44.0%10.8M234 5-FU CI 0.8347.9%11.4M234 S-1 0.8552.5%12.3M236 CPT-11+CDDP HR1-yrMSTn †: one-sided log-rank test (superiority) non-inferiority <0.001 ‡: multiplicity adjusted by Holm’s method Significance level ‡ 0.05 0.025 Boku, ASCO 2007

24. No. of patients Incidences(%) of Gr.>3 Adverse Events within 6 months 5.63.83.9 0.941.5 0 5.665.01.3 12.839.315.5 1.34.70.4 7.7 0 09.40 S-1CPT-11+CDDP5-FU CI 234 236234 Treatment related death*0.41.30 Leukocytes Neutrophils Hemoglobin Platelets Infection without neutropenia Infection with Gr.3 or 4 neutropenia Febrile neutropenia * Judged by Data and Safety Monitoring Committee Boku, ASCO 2007

25. 1.703.0Stomatitis 5.620.56.9Nausea 7.79.00.4Diarrhea 12.432.912.5Anorexia 5.110.31.7Fatigue 4.72.64.7AST 3.42.63.4ALT 4.31.33.0Bilirubin 0.92.10Creatinine 5.222.66.5Hyponatremia Incidences(%) of Gr.>3 Adverse Events within 6 months No. of patients S-1CPT-11+CDDP5-FU CI 234236234

26. JCOG 9912 S-1 is non-inferior to CI 5-FU Cisplatin/irinotecan better than CI 5-FU Cisplatin/irinotecan (this regimen) more toxic S-1 results approximate combination therapy

27. SPIRITS Trial 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 Narahara, ASCO 2007

28. Months Estimated probability (%) 11.013.0 Overall Survival S-1S-1+CDDP No. of pts 150148 MST 11.013.0 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 Narahara, ASCO 2007

29. Progression-Free Survival Log-rank p-value: <0.0001 HR: 0.567 [ 95% CI: 0.437 – 0.734] Estimated probability (%) Months 6.04.0 S-1S-1+CDDP No. of pts 150148 PFS 4.06.0 Narahara, ASCO 2007

30. Overall Response No. Response Overall RR CRPRSDPDNE S-110613234 5 31 % S-1+CDDP8714613243 54 %  Criteria : RECIST (Extramural Review) Fisher’s Exact Test p-value: 0.0018 Narahara, ASCO 2007

31. IRIS GC0301/TOP-002 Randomized phase III study 326 patients randomized S-1 alone vs. S-1 plus irinotecan Response rate –26.9% vs. 41.5% 1-year survival –44.9% vs. 52.0%, NS 22% of patients were censored Imamura, GI ASCO 2008

32. Metastatic Gastric Cancer We still don’t know the optimal regimen for patients with metastatic disease –Combination vs. sequential therapy –Role of oral fluoropyrimidines, newer platinum agents, taxanes More S-1 studies are forthcoming –FLAGS - 1053 pts, accrual completed 3/07 –5-FU/cis vs. S-1/cis Trials of biologics are underway –AVAGAST – capecitabine/cisplatin with or without bevacizumab –CALGB 80403 – FOLFOX-cetuximab, cisplatin/irinotecan- cetuximab, ECF-cetuximab –ToGA – capecitabine/cisplatin with or without trastuzumab