1. Weijing Sun, MD Associate Professor of Medicine Director of GI Medical Oncology Abramson Cancer Center University of Pennsylvania Gastroesophageal Adenocarcinoma Are We on the Right Track?

2. Abstract 4515: –Chemoradiation of Resected Gastric Cancer: A 10-Year Follow- up of the Phase III Trial INT-0116 (SWOG 9008). Macdonald J.S. et al. Abstract 4513: –Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356). Leichman L, et al Abstract 4514: –Updated results of 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 (JCOG 9912). Fuse N., et al. Abstract 4512: –Analysis of survival with modified docetaxel, cisplatin, fluorouracil (mDCF), and bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma: Results of a phase II clinical trial. Kelsen D. et al

3. In USA: ~35,000 cases/yr; ~25,000 deaths/yr Globally: ~1 million cases/yr; ~0.7 million deaths/yr Decreased incidence: –ESCC and distal gastric adenocarcinomas Increased incidence: –Adenocarcinoma of the distal esophagus –Adenocarcinoma of the GE junction Surgery is the only potentially curative maneuver Evidence suggests peri-operative therapy improves survival Jemal a, et al. CA Cancer J Clin, 2008 58:71-96 Parkin DM et al. CA Cancer J Clin, 2005, 55:74-108 Gastroesophageal Cancers

4. Differences in the East vs. West –Etiology –Ethnic –Pharmacogenetics Molecular/Biology Characteristics –Bio-etiology –Carcinogenesis –Tumor biology –‘Microenviroment’: angiogenesis vs. stroma Important Factors in Therapy of Gastroesophageal Cancer

5. 5-Year Survival AJCC StageUSJapanJapanese-Americans IA78%95% IB58%86%75% II34%71%46% IIIA20%59%48% IIIB8%35%18% IV7%17%5% Overall28%60%42% Cancer 2000, 88:921-32 > 15 lymph nodes resected

6. Molecular Biology of Gastroesophageal Cancer Chromosomal gains and losses Rb mutations Her-2 expression EGFR overexpression Cyclin D1 overexpression C-Met p16, p27 mutations COX-2 overexpression Adhesion proteins (E-cadherin,  - &  -catenin mutations)

7. Goals in Treating Gastroesophageal Adenocarcinoma For metastatic/advanced disease: –Increase efficacy, decrease toxicity For locally advanced disease: –Improve cure & survival rate –Increase resectability –The extent of tumor down-staging after CTX and XRT is the most important prognostic indicator for DFS and OS

8. SCHEMA RESECTED STAGE IB-IV (MO) GASTRIC ADENOCARCINOMA RANDOMRANDOM OBSERVATION 5-FU/LV RADIATION 5-FU/LVX2 5-FU/LV 4,500 cGy Abstract 4515: INT 0116 Current report gives results with median follow-up 11 years Provides expanded subset analyses: –T Stage, N Stage, Localization, D-Level of resection, Diffuse vs. Intestinal pathology, Male vs. Female, Maruyama Index

9. Overall Survival by Treatment Arm

10. Abstract 4515: INT 0116 OS hazard ratio 95% CIp- value median obs (months) median RX (months) 2001 (3 yrs)1.321.06-1.640.0052736 2004 (7 yrs)1.311.08-1.610.0062635 2008 (11 yrs)1.311.09-1.590.0052735 DFS 20011.521.23-1.86< 0.0011930 20041.521.23-1.85< 0.0011930 20081.521.29-1.83< 0.0011927 Macdonald JS, et al. NEJM 2001, 345:725-730 Macdonald JS, et al, ASCO 2004 Macdonald JS, ASCO 2009,

12. (98/305=32%) (71/127=56%)

13. Abstract 4515: INT 0116 Toxicities Major Toxicities –Hematologic148 (54%) –GI 89 (33%) –Flu-like25 (9%) –Infection 16 (6%) –Neurologic12 (4%) –Cardiovascular11 (4%) –Pain9 (3%) –Metabolic 5 (2%) –Hepatic 4 (1%) –Death3 (1%) Macdonald JS, et al. NEJM 345:725-730, 2001

14. Second Tumor Sites CHEMORADS (25) *CONTROL (8) Skin 6 (2 Melanoma) Pancreas 2 Colorectal 4 Basal Cell 2 Prostate 4 Breast 1 Bladder 3 Lung 1 Heme 3 (2 Lymphoma; 1 MDS) Bone Marrow 1 Breast 1 Renal 1 Lung 1 Renal Pelvis 1 Larynx 1 Unknown Primary 1 *21 Patients (no statistically significant differences) Abstract 4515: INT 0116

15. Abstract 4515: INT 0116 Summary OS and DFS for chemoradiation remain highly significant With >11 years follow up No significant late effects with 5-FU based Chemo/XRT Second tumors are considered not treatment related. However, needs to be assessed in ongoing studies Subset analyses show Diffuse histology (Women+Diffuse type) appears negative predictor for treatment benefit Questions for improving outcome: More effective cytotoxic regimen(s) Histopathologic- and biologic characteristic-based- treatment Pre-operative chemo- or chemoradiation

16. Two Large Phase III Randomized Peri-Operative Chemotherapy Studies MAGIC: –Operable adenocarcinoma of the stomach, gastroesophageal junction, or lower esophagus,  Stage II (M0) –ECF*  Surgery  ECF (N= 250) vs. Surgery alone (N= 253) Epirubicin 50 mg/m² IV,day 1; Cisplatin 60 mg/m² 4-hour infusion, day 1; 5-FU, 200 mg/m²/day CI days 1-21) (ACTS-GC) –S-1 vs. Surgery Alone after D2 Gastrectomy Cunningham D, et al. N Engl J Med. 2006;355:11-20. Sakuramoto S N Eng J Med 2007, 357:1810-20

17. OSHR95% CIp 2006 (3 yrs)0.750.60-0.930.009 PFS 2006 (3 yrs)0.660.53-0.810.0001 MAGIC Trial: Pre- and Postoperative Chemotherapy CSCSp MOS24 months20 months0.009 5-year OS36%23%-

18. There is no info about histopathology Type: Diffuse vs. intestinal

19. ACTS-GC : S-1 vs. Surgery Alone after D2 Gastrectomy Curative Gastrectomy (D2) Within 6 wks after Surgery –Stratify: Stage (II, IIIA, IIIB), Institution S-1 (N=529) vs. Surgery alone (N=530). –S-1: Tegafur –fluoropyrimidine, Gieracil—DPD inhibitor, Oteracil– orotate phosphoribosyltranserase (reduce GI toxicity) S-1 is effective as adjuvant for EAST ASIAN Pts. Undergone a D2 dissection Sakuramoto S N Eng J Med 2007, 357:1810-20

20. Phase III Peri-Op Studies 5-yr Survival 3-yr Survival  INT 0116 5-FU/XRT50 %9 % Surgery41 % MAGIC CSC36 %13 % Surgery23 % ACTS-GC (S-1) S-1*80.5 %10.4 % Surgery70.1 % *S-1 efficacy has not been shown clearly in WESTERN gastroesophageal cancer patients in either adjuvant or metastatic setting (e.g. FLAGS study)

21. C80101: Randomized Phase III Adjuvant Trial FU/LV XRT+CIFU FU/LV x2 ECF XRT+CIFU ECF x2 Biologic markers collected: TS, ERCC-1, MSI, EGFR, COX-2 R Just closed recently (last week) at full accrual N=824

22. Neoadjuvant Chemoradiation Trimodality Increases overall survival Pathological complete response (pCR) as the predictor for overall outcome –Meta-analysis: –CALGB 9781: Trimodality vs. surgery alone in Esophageal CA cisplatin 100 mg/m2, day 1; 5-FU 1,000 mg/m2/d x 4 days weeks 1 and 5; concurrent with radiation therapy (50.4 Gy) Followed by esophagectomy; More chemotherapy after surgery –planned to enroll 475 pts, only 56 patients (30 in the trimodality arm and 26 in the surgery alone) –mOS 4.48 yrs vs. 1.79 yrs (p=0.002) –pCR: 10/30, PR: (micro 2/30, macro 8/30), SD: 2/30, PR: 2 Ajani JA, et al. JCO 2005:1237 Reed VK, et al. IJROBP 2008, 71:741 Gebski V, et al Lancet Oncol 8:226-234, 2007 Tepper J, et al. JCO 2008; 26:1086

23. Abstract 4513: S0356 Neoadjuvant for EAAC New agent (oxaliplatin) may improve efficacy and decrease toxicity Pathology complete response is predictive and prognostic factor for the overall outcome. Study design: –Assess pCR rate (>25%), PFS and OS. –Assess frequency and severity of toxicities –Explore intratumoral parameters thought to be relevant to pCR (ERCC-1, XPA, TS, γ GT and γ GCS)

24. Abstract 4513: S0356 Study design: –Chemo: OXP 85 mg/m2 IVPB days 1, 15 and 29 CI 5FU 180 mg/m2/days 8-43. –EBRT d 8-43 (25 fractions) –Esophagectomy 2-4 weeks after CTX/XRT –Second cycle of OXP and CI 5FU 4-6 weeks postop Follow-up observation at 3 month intervals Mandated central pathology review pre-op and post-op

25. Abstract 4513: S0356 Result (N=98): –pCR: 34% (31 pts. Central review confirmed), 9 patients (10%) had either T in situ N0M0 or T1N0M0: met the 1 0 end point. –The regimen of OXP and CI 5FU with EBRT is safe, less toxic (gr 3/4) 43% overall: 39% GI, 22% fatigue, 17% pulmonary,16% hematologic,14% mucositis, 3% neurologic –Surgical mortality 2.6%: acceptable 38 patients (42%) underwent postoperative chemotherapy. (Sequence of radiation vs. chemotherapy is debatable) (MAGIC Trial: only 54.8 % had post-surgery chemotherapy)

26. Trimodality with newer agent (oxaliplatin/5- FU/XRT) has increased pCR and relative less toxicity, PFS and OS remain to be determined –Too early to make conclusion whether this regimen is superior to cis/5-FU/XRT Molecular parameters which may help to determine how individuals should be treated are still pending. Needs larger (randomized study) to confirm Abstract 4513: S0356 Summary

27. Abstract 4514: (JCOG 9912). Assumed: –S-1 no-inferiority to 5-FU (+/- 5%) –CPT-11+CDDP: superior to 5-FU (+10% survival) First reported in 2006 ASCO (N=704) Study Design: –5-FU (800 mg/m2/day, ci, days 1-5, q 4 wks); –CPT-11 & CDDP (CPT-11, 70 mg/m2, div, days 1&15, Cis 80 mg/m2, div, day 1, q 4 weeks); –S-1 (40 mg/m2, po, bid, days 1-28, q 6 weeks)

28. No. of patients Gr >3 AE (%) within 6 mos 5.63.83.9 0.941.50 5.665.01.3 12.839.315.5 1.34.70.4 7.70 09.40 S-1CPT-11+CDDP5-FUci 234236234 Treatment-related death*0.41.30 Leukocytes Neutrophils Hemoglobin Platelets Infection without neutropenia Infection with Gr 3 or 4 neutropenia Febrile neutropenia Abstract 4514: (JCOG 9912)

29. ASCO 2006: S-1 showed non-inferiority to 5-FU ci in survival – mild toxicities, – favorable results of RR, TTF, NHS and PFS CPT-11+CDDP did not show superiority to 5-FU ci in survival – substantial toxicities causing treatment failure – favorable results of RR, TTF, NHS and PFS, Abstract 4514: (JCOG 9912)

30. neventMST1-ysr2-ysr Stratified Cox HR (95% CI) Unadjusted 1-sided stratified logrank p- value － － 5-FUci 23422410.8M44% 14% -- － － CP 23622012.3M53% 18% 0.82 (0.68-0.99)0.019 (superiority) － － S-1 23421611.5M48%21%0.83 (0.68-1.00)0.023 (superiority) Abstract 4514: (JCOG 9912) Update

31. 5-FUci vs. CPT-11+CDDP5-FUci vs. S-1 No. of patients Hazard ratio for death Total 704 Age <65 372 ≥65 332 Tumor status Unresectable 567 Recurrent 137 PS 0 454 1,2 250 No. of metastatic sites 0,1 305 ≥2 399 Target lesion - 173 + 531 Macroscopic type 0,1,2 219 3,4,5 485 Histologic type intestinal 323 diffuse 381 Peritoneal metastasis - 472 + 232 0 0.5 1.0 1.5 2.0 CP better 5-FUci better S-1 better 5-FUci better

32. S-1 is considered as a standard chemotherapy for East Asian patients with unresectable or recurrent gastric cancer. –S-1 has been confirmed (single agent or in combination with CDDP) in the Eastern patient population. –S-1 benefits have not been shown in Western populations including most recent FLAGS study CP combination confirmed platinum efficacy Kiozumi W, et al: Lancet Oncol. 2008;9(3):215-21. Ajani JA, et al GI Cancer Sym 2009: Abs 8 Abstract 4514: (JCOG 9912) Summary

33. Abstract 4512: Rationale and Study Design Combination chemotherapy with increased response rates (30- 60%), Short duration of response, & increased toxicity : DCF, ECF (ECX, EOF, EOX), FP (XP), Cis-Iri DCF improved RR, PFS, and OS FDA and European approval in 1 st line treatment High incidence of gr 3/4 hematologic and non-hematologic (~80%) toxicity limits the use of DCF Modified DCF regimen to reduce toxicity Bevacizumab is approved with chemotherapy for the treatment of colorectal, lung and breast cancer Phase II studies with different combination suggested some benefits (Cisplatin/Irinotecan & docetaxel/Irinotecan) Shah MA et al, JCO 2006 Fuchs CS et al, ASCO 2008, Abs 4552

34. Abstract 4512: End Points: –Primary: To improve 6-month PFS from 43% to 63%. –Secondary: RR, median PFS, 1-year Survival, and OS, the safety of mDCF + BEV in patients with unresectable or metastatic GE cancer DrugDose (mg/m 2 )Schedule Bevacizumab10 mg/kgDay 1 Docetaxel40Day 1 IVPB (60 min) Fluorouracil400Day 1 IVPB (30 min) Leucovorin400IVP day 1 Fluorouracil1000IVCI x 48 hours Cisplatin40Day 3 IVPB (30 min)

35. Abstract 4512: N=44 (measurable=39) Mean follow up 13 months 6 month PFS: 83 % (68-92%) RR: 67% (50-81%), SD: 31% (17-48%), PD: 2% Median PFS 12.8 month (8.9-16.4 months) Median OS 16.3 mo (11.4 mo – not reached) Gr 3/4 toxicity: Neutropenia 51%, Febrile Neutropenia 4%,Thrombocytopenia 16%, Anemia 11% (DCF 82%, 29 %, 8%, 28%) Gr 3/4 DVT 31%, Gastric Perforation 2%, Bleeding 2%

36. StudyNo of Pts.ScheduleEfficacyGr. 3/4 Toxicity Jhawer et al 44Bevacizumab 10 mg/kg + Taxotere 40 mg/m2 + 5-FU 400 mg/m2 + LV 400 mg/m2, Day 1 + 5-FU 1000 mg/m2/d x 2 days + cisplatin 40 mg/m2, Day 3 q 2 wk (1 cycle = every 3 treatments 6 month PFS: 83 % RR: 67% SD: 31% MPFS 12.8 mo, MOS 16.3 mo Neutropenia 51%, Febrile Neutropenia 4%,Thrombocytopenia 16%, Anemia 11% DVT 31%, Gastric Perforation 2%, Bleeding 2% Jhawer et al 47Bevacizumab 15 mg/kg day1; CPT-11 65 mg/m2 days 1,8; Cis 30 mg/m2 days 1,8 ORR: 65% MPFS: 8.3 mo, MOS: 12.3 mo Neutropenia 29%, Thrombocytopenia 16%, Anemia 11% DVT 28%, Gastric Perforation 6%, Bleeding 4% Enzinger et al 35Bevacizumab 10 mg/kg, Day 1 + Taxotere 30 mg/m2 + cisplatin 25 mg/m2 + irinotecan 50 mg/m2, Days 1 & 8 q 3 wk ORR: 69%neutropenia (29%), febrile neutropenia (14%), diarrhea (34%) El Rayes et al 8Bevacizumab 7.5 mg/kg + Taxotere 70 mg/m2 + Eloxatin 75 mg/m2 q 3 wk ORR: 50%neutropenia (38%), fever (13%), acute neuropathy (13%), hypertension (13%) Sun, et al44Sorafenib 400 mg BID, Days 1-21+ Taxotere 75 mg/m2 q 3 wk + Cisplatin 75 mg/m2 q 3 wk ORR: 41% MPFS: 5.8 mo MOS: 13.6 mo leukopenia 41%, infection 11%, hand- foot reaction 11%, Nausea 16% Pinto et al45Cetuximab* 250 mg/m2 + Taxotere 75 mg/m2 + cisplatin 75 mg/m2 Day 1 q 3 wk ORR: 40.5% 3-mo PFS: 80% neutropenia (45.8%), febrile neutropenia (22.9%), asthenia (22.9%), hyponatremia (20%), hypokalemia (16%) Shah MA et al JCO 2006, 24:5201; El Rayes BF, et al. J Clin Oncol 2008;26 (abstract 15608). Enzinger PC, et al. J Clin Oncol 2008;26 (abstract 4552). Pinto C, et al. J Clin Oncol 2008;26 (abstract 4575). Sun W, et al. J Clin Oncol 2008;26 (abstract 4535). Other Studies Show Advances in Outcomes with Biologics

37. Summary Both adjuvant and neoadjuvant therapy beneficial in Gastroesophageal Adenocarcinoma Newer chemotherapy agents showed advances in systemic chemotherapy (Oxaliplatin, S-1, Docetaxel, …) Pharmacogenetics and biology of both host and tumor are important for tailoring the patient’s needs Biological (antiangiogenesis) agents hold promise, but phase III studies are needed.

38. Conclusion Peri-operative therapy is ‘standard’ approach More effective chemotherapy regimen may benefit more at adjuvant or neoadjuvant setting (CALGB 80101) New cytotoxic agents may increase efficacy and increase pCR in peri-operative setting and less toxicity. Biological agents show very encouraging benefits in metastatic disease setting –Bevacizumab (Tumor environment) –Trastuzumab in Her-2+ gastric cancer (ToGA, LBA4509) (Tumor Biology)

39. On-going Studies: MAGIC –B (based on data of combination with bevacizumab and other antiangiogenics) –Role of bevacizumab pre-op setting (ECF + pre-op bevacizumab) CRITICS (based on data of INT-0116 and MAGIC; and find out the optimal sequence and duration of chemoradiation) –Preoperative chemo and post operative chemoradiation Phase III trails of Chemo +/- antiangiogenesis Future: individualized therapy based on natural history + individual (host and tumor) biology in both Peri-op and advanced settings.Conclusion