1. Systemic Therapy for Gastric Cancer Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

2. GASTRIC CANCER 2009 #New Cases (rank) # Deaths (rank) United States (2008)* 21,500(#14) 10,800(#13) Worldwide (2002)° 934,000(#4) 700,000(#2) * Jemal, et. al. CA Cancer J Clin 2008;58:71 ° Parkin, et. al. CA Cancer J Clin 2005;55:75

3. Gastric Cancer Mortality: Regional Differences Jemal et al. CA Cancer J Clin. 2006. 56:106. United States Chile China Columbia Japan Poland Venezuela Germany France Hungary

6. Gastric Cancer: Pathology Intestinal type Cohesive cells Forms discrete mass Distal stomach Endemic Better prognosis Diffuse type Lack cell cohesion Infiltrates without discrete mass Proximal stomach Not endemic Worse prognosis 1. Adenocarcinomas (90%), lymphoma, leiomyosarcoma 2. Adenocarcinoma can be subdivided:

7. Gastric Cancer Survival by Stage National Cancer Data Base 1985-1996 IA IB II IIIA IIIB IV

8. CASE A 62 yo man presents with new metastatic gastric adenocarcinoma (liver mets). PS = 0 to 1. Your choice of front-line therapy: A. Docetaxel, cisplatin, 5-FU (DCF) B. Irinotecan, cisplatin or FOLFIRI C. Epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine) D. Capecitabine/cisplatin (5-FU/cisplatin) E. 5-FU, leucovorin, oxaliplatin (FOLFOX) F. Single agent therapy G. Other

9. Gastric Cancer: Single Agent Chemotherapy 18-31%Irinotecan 17-24%Docetaxel 5-21%Paclitaxel 19%Cisplatin 17%Doxorubicin 30% Mitomycin C 11%Methotrexate 21%5-Fluorouracil Response Rate Drug

10. 5-FU and Cisplatin in Advanced Gastroesophageal Adenocarcinoma Trials Ohtsu et al. J Gastro 2007 JapanEuropeUS/Europe N105134112 RR34%20%23% Median PFS 3.9 mos. 4.1 mos. 3.7 mos. Median OS 7.3 mos. 7.2 mos. 8.5 mos.

11. FAMtx vs. ELF vs. 5FU/CDDP in Advanced Gastric Cancer 399 patients 399 patients with advanced with advanced disease disease Response Median Rate Survival FAMtx12%9 mos ELF9%7 mos 5-FU+CDDP20%9 mos

12. Gastric Cancer: Chemotherapy Versus Supportive Care AuthorRegimenNo.ofPts. Median Survival (mos) PyrhonenFEMTX BSC 17 19 12 3 MuradFAMTX BSC 30 10 10 3 GlimeliusELF BSC 10 8 10 4 ScheithauerELF BSC 18 19 >7.5 4

13. 5-FU/CDDP vs. Capecitabine/CDDP in Advanced Gastric Cancer Kang et al. ASCO 2006 NRR%MedianTTP,mosMedianOS,mos 5-FU/CDDP137295.09.3 Capecitabine/CDDP139415.6*10.5* *P = N.S.

14. S-1 Oral fluoropyrimidine: tegafur, CDHP, OXO Oral fluoropyrimidine: tegafur, CDHP, OXO Tegafur converted to 5-FU Tegafur converted to 5-FU CDHP inhibits DPD in gut (prevents degradation) CDHP inhibits DPD in gut (prevents degradation) OXO inhibits phosphorylation of 5-FU in gut (reduces diarrhea) OXO inhibits phosphorylation of 5-FU in gut (reduces diarrhea) Asian and Caucasian population have different rates of activation of tegafur to 5-FU Asian and Caucasian population have different rates of activation of tegafur to 5-FU  CYP2A6  Different polymorphisms for Asians vs. Caucasians

15. S-1/CDDP in First-Line Advanced Gastric Cancer (FLAGS) RANDOMIZE S-1Cisplatin 5-FUCisplatin 1,000 patients worldwide:

16. FLAGS: Results Ajani et. al. GI ASCO 2009 Outcome # pts response rate median PFS median OS S-1+Cisplatin52129.1% 4.8 mos 8.6 mos p=0.40p=0.92p=0.20 5-FU+Cisplatin50831.9% 5.5 mos 7.9 mos

17. ECF Versus FAMtx in Advanced Esophagogastric Cancer J Clin Oncol 1997; Br J Cancer 1999 ECF: Epirubicin 50 mg/m 2 q 3 wks q 3 wks CDDP 60 mg/m 2 q 3 wks q 3 wks 5- FU 200 mg/m 2 /d C.I. Response Rate Median Survival 1 Yr Survival Grade 3/4 Neutropenia ECF45% 8.7 mos 36%36%274 patients with adeno- carcinoma FAMtx21% 5.7 mos 21%58%

18. REAL-2 Trial Design for Advanced and Metastatic Gastro-Esophageal Cancer ECFEEF EEXECX 2x2 multifactorial design X: Xeloda 1250 mg/m 2 daily E: Eloxatin 130 mg/m 2 every 3 weeks 1,000 patients randomized to: N Eng J Med 2008

19. Overall Survival (Per-protocol): Fluoropyrimidine comparison NMedian1 year95% CI 5FU4849.639.4%35.0 - 44.0 Capecitabine48010.944.6% 40.1 – 49.0 HR 0.86 (0.8 – 0.99) HR for ITT population = 0.88 (0.77 – 1.00) p= 0.058 N Eng J Med 2008

20. Overall Survival (Per-protocol): Platinum comparisonNMedian 1 year 95% CI Cisplatin49010.040.1%35.7 - 48.4 Oxaliplatin47410.443.9% 39.4 – 49.0 HR 0.92 (0.8 – 1.10) HR for ITT population = 0.91 (0.79-1.04) p=0.159 N Eng J Med 2008

21. Survival by Regimen ECF vs EOX (ITT)Arm OS (m) 1 year survival (95% CI) p-valueHR ECF EOX 9.9 11.2 37.7 (31.8-43.6) 46.8 (40.4-52.9)0.020 1 0.80 (0.66-0.97)

22. Phase II Studies of 5-FU/Oxaliplatin in Advanced Gastroesophageal Adenocarcinoma StudyRegimenN ORR (%) TTP (months) Median OS (months) Louvet et al 1 FOLFOX-64145 6.28.6 Al-Batran et al 2 FOLFOX-64143 5.69.6 Chao et al 3 FLOX5556 5.210.0 DeVita et al 4 FOLFOX-46138 7.111.2 Lordick et al 5 FUFOX4854 6.511.4 Cavanna et al 7 FOLFOX-45643 6.010.0 1. Louvet et al. J Clin Oncol. 2002. 20:4543. 2. Al-Batran et al. J Clin Oncol. 2004. 22:658. 3. Chao et al. Br J Cancer. 2004. 91:453. 4. De Vita et al. Br J Cancer. 2005. 92:1644. 5. Lordick et al. Br J Cancer. 2005. 93:190. 6. Jatoi et al. ASCO, 2005. Abstract 4059. 7. Cavanna et al. Am J Clin Oncol. 2006. 29:371. NCCTG = North Central Cancer Treatment Group;

23. 5-FU, LV, Oxaliplatin vs. 5-FU, LV, Cisplatin in Advanced Gastroesophageal Adenocardinoma Al-Batran et al, J Clin Oncol 2008 RANDOMIZE 5-FU 2,600mg/m 2 /24hr Leucovorin 200mg/m 2 Oxaliplatin 85mg/m 2 5-FU 2,000mg/m 2 /24hr Leucovorin 200mg/m 2 Cisplatin 50mg/m 2 220 patients with advanced gastric cancer: Q 2 weeks

24. FLO vs FLP in Advanced Gastroesophageal Cancer Al-Batran et al. RRMedianPFSMedianOS FLO35% 5.8 mos 10.7 mos FLP25% 3.9 mos 8.8 mos P-value0.077NS

25. FLO vs FLP in Advanced Gastroesophageal Cancer Al-Batran et al. Grade  3 Toxicity FLON=112FLPN=102P-value Nausea (%) 4.58.80.003 Vomiting (%) 2.75.90.002 Fatigue (%) 3.66.90.03 Neurosensory (%) 14.32.0<0.001 Any grade renal (%) 10.734.30.03

26. FLO vs FLP: Patients >65 years (N=94) Al-Batran et al. RR Median PFS Median OS FLO41% 6.0 mos 13.9 mos FLP17% 3.1 mos 7.2 mos P-value0.0120.0290.083

27. Irinotecan, 5-FU, LV vs. Cisplatin, 5-FU, LV in Advanced Gastroesophageal Adenocarcinoma Dank et al. Ann Oncol 2008 NRRMedianTTPMedianOS FU/LV/IRI17032% 5.0 mos 9.0 mos FU/LV/CDDP16326% 4.2 mos 8.7 mos P-value0.230.0880.53

28. CPT-11 and Cisplatin in Advanced Gastric Cancer Author No. of Pts RR G3-4 Diarrhea G4 Neutropenia Boku* 44 48% 20% 57% Takincki 19 38% -- -- Ajani 36 58% 22% 15% * Median survival = 9 mos.

29. Taxanes in Advanced Gastric CancerAgentAuthorNo.ofPts. RR (%) TaxolOhtsu1620 TaxolAjani3317 TaxolCascinu3622 TaxotereMavroudis3020 TaxotereMai6324 TaxotereECOG4117 TaxotereEORTC3724

30. Docetaxel 75 mg/m 2 + Cisplatin 75 mg/m 2 + 5-FU 750 mg/m 2 /d CI days 1-5 every 3 weeks n=221 n=224 RANDOMIZATION V325: Phase III Study of DCF J Clin Oncol 2006 Cisplatin 100 mg/m 2 + 5-FU 1000 mg/m 2 /d CI days 1-5 every 4 weeks

31. V325: DCF in Gastric Cancer DCFN=221CFN=224P-value Response Rate 37%25%0.01 Median TTP (months) 5.63.70.001 Median OS (months) 9.28.60.02 J Clin Oncol 2006

32. V325: DCF in Gastric Cancer J Clin Oncol 2006 33%46% Early treatment discontinuation 12%22% Withdrawal of Consent 21%24% Discontinuation due to adverse event 12%29% Febrile Neutropenia 57%82% Grade 3/4 Neutropenia CFDCF

33. Phase II Study of Taxotere, Cisplatin, CPT-11 (TPC) in Metastatic Esophagogastric Adenocarcinoma Taxotere 30 mg/m 2 Cisplatin 25 mg/m 2 CPT-11 50 mg/m 2 weekly x 2 then one week rest 56 patients 56 patients Response rate = 54% Response rate = 54% Median progression-free survival = 7.1 months Median progression-free survival = 7.1 months Median overall survival = 12 months Median overall survival = 12 months Grade 3/4 neutropenia = 21% Grade 3/4 neutropenia = 21% Enzinger et al. Ann Oncol. 2009

34. Do you use any of the following “biologic” therapies in advanced gastric cancer study? A. A. Bevacizumab B. B. Cetuximab C. C. Panitumumab D. D. Erlotinib E. E. Sunitinib F. F. Sorafenib G. G. None

35. Phase II Study of Irinotecan, Cisplatin, Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma Shah et al. J Clin Oncol. 2006 Irinotecan 65mg/m2 d1,8 Cisplatin 30mg/m2 d1,8 Bevacizumab 15mg/kg d1 47 patients RR = 65% Median TTP = 8.3 mos Median OS = 12.3 mos Grade 3/4 HTN = 28% Two patients had gastric perforation One patient had significant UGI bleed Q 21 days

36. Phase II Study of mDCF and Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma Jhawer et al. GI ASCO 2009 Docetaxel 40 mg/m2 d1 5-FU 400 mg/m2 5-FU 1000 mg/m2/d d 1,2 Bevacizumab 15mg/kg d1 Cisplatin 40 mg/m2 d3 44 patients RR = 67% Median TTP = 12 mos Median OS = 16 mos grade 3/4 neutropenia 51% vs. 82% Q 14 days

37. Taxotere, Cisplatin, CPT-11, Bevacizumab (TPCA) in Metastatic Esophagogastric Adenocarcinoma Taxotere 30 mg/m 2 d1, 8 Cisplatin 25 mg/m 2 d1, 8 CPT-11 50 mg/m 2 d1, 8 Bevacizumab 10 mg/kg d1 q 3 weeks 33 patients 33 patients Response rate = 63% Response rate = 63% Enzinger et al. GI ASCO 2008

38. Weekly Docetaxel and Bevacizumab (AvaTax) in Previously Treated Metastatic Esophagogastric Cancer Enzinger et al. Docetaxel 35mg/m2 d1, 8, 15 Bevacizumab 5mg/kg d1, 15 40 pts – previously treated 40 pts – previously treated RR = 20% RR = 20% Median PFS = 3.5 mos. Median PFS = 3.5 mos. Median OS = 9.3 mos. Median OS = 9.3 mos. Grade 3/4 bleeding = 18% Grade 3/4 bleeding = 18% One patient (2.5%) had gastric perforation One patient (2.5%) had gastric perforation Q 28 days

39. Bezacizumab in First-Line Advanced Gastric Cancer (AVAGAST) RANDOMIZE CapecitabineCisplatinPlacebo CapecitabineCisplatinBevacizumab 760 patients with previously untreated disease: Primary Endpoint: Overall Overall Survival Survival

40. Phase III Study of IMC-1121B in Second-Line Gastric Cancer RANDOMIZE IMC-1121B Placebo 615 patients who failed FU or CDDP-based therapy Primary Endpoint: Overall Overall Survival Survival

41. Phase II Study of Erlotinib in Gastroesophageal Adenocarcinoma SWOG 0127 Dragovich et al. J Clin Oncol. 2006 GE jxn (N=43) Gastric (N=25) Response Rate 9%0% Median TTF 2 mos. 1.6 mos. Median OS 6.7 mos. 3.5 mos. 68 pts with previously untreated disease:

42. Phase II Study of FOLFIRI-Cetuximab in Advanced Gastroesophageal Adenocarcinoma Pinto et al. Ann Onc 2007 38 patients 38 patients OR = 44% OR = 44% Median TTP = 8 mos. Median TTP = 8 mos. Median expected OS = 16 mos. Median expected OS = 16 mos. Grade 3/4 neutropenia = 42% Grade 3/4 neutropenia = 42% Grade 3/4 diarrhea = 8% Grade 3/4 diarrhea = 8%

43. Cetuximab in Advanced Gastroesophageal Adenocarcinoma: EXPAND Trial RANDOMIZE CapecitabineCisplatin CapecitabineCisplatinCetuximab 870 patients with previously untreated disease: Primary Endpoint: Progression-Free Progression-Free Survival Survival

44. Trastuzumab in Gastric Cancer RANDOMIZE CapecitabineCisplatin CapecitabineCisplatinTrastuzumab 584 patients with HER-2 positive, previously untreated advanced gastric cancer: Primary endpoint: Overall Survival

45. Paclitaxel vs. Placlitaxel/Lapatinib in Second-line ErbB2 Amplified Gastric Cancer RANDOMIZE Weekly Paclitaxel +Lapatinib 314 patients following first-line therapy: Primary endpoint: Overall Survival

46. c-Met Pathway in Human Cancer

47. MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma Smollen et al PNAS, 2006

48. CASE 56 yo man presents with new resectable distal gastric adenocarcinoma. CT scan demonstrates gastric wall thickening without metastatic disease. You recommend: A. Surgery alone B. Pre-operative ECF (ECX, EOX) C. Pre-operative 5-FU/CDDP D. Surgery followed chemotherapy E. Surgery followed by 5-FU-based chemotherapy plus external beam radiotherapy

49. Adjuvant Therapy for Gastric Cancer: Meta-analysis Earle, 1999

50. Adjuvant S-1 in Stage II/III Gastric Cancer Sakuvamoto et al, NEJM 2007 RANDOMIZE S-1 80 mg/m2 qd x 4 weeks followed by 2 week rest x 1 year observation 1,059 patients following resection of stage II/III gastric cancer

51. Adjuvant S-1 in Gastric Cancer Sakuvamoto et al. 3-year Relapse-free Survival 3-year Overall Survival S-172%80% Observation60%70% P-value<0.0010.003 Hazard Ratio (95% CI) 0.62 (0.50-0.77) 0.68 (0.52-0.87)

52. Adjuvant Radiotherapy in Resectable Gastric Cancer Hallissey et al, 1994 Locoregional Relapse (%) 5-Year Survival Observation57%20% Radiation (45 Gy)34%12% FAM chemotherapy 41%19% 436 patients following gastrectomy randomized to:

53. Intergroup 0116 RESECTED STAGE IB-IV (MO) GASTRICADENOCARCINOMA RANDOM OBSERVATION 5-FU/LV 5-FU/LV 5-FU/LV 5-FU/LV 5-FU/LV RADIATION 5-FU/LV x2 4,500 cGy 4,500 cGy

54. 3-Year RFS (%) Surgery alone 30 Post-op 5-FU/RT 48 P<0.0001 54% improvement in relapse-free survival54% improvement in relapse-free survival

55. 3-Year OS (%) Surgery alone 40 Post-op 5-FU/RT 50 P=0.01 32% improvement in overall survival

56. Intergroup 0116ObservationTreatmentLocal5121 Regional12676 Distant3236 Sites of Recurrence

57. Conclusions from Intergroup 0116 Post-op. chemo-RT is a potential standard in therapy of resectable gastric cancer. Post-op. chemo-RT is a potential standard in therapy of resectable gastric cancer. Toxicity of post-op. chemo-RT is acceptable. Toxicity of post-op. chemo-RT is acceptable. Post-op. chemo-RT improved locoregional recurrence > distant recurrence. Post-op. chemo-RT improved locoregional recurrence > distant recurrence.

58. Pre -RT Chemo (1 cycle) Chemo with RT (45 Gy) Post- RT Chemo (2 cycles) Epirubicin 50 mg/m 2 d1 50 mg/m 2 d1 A Pilot Study of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma Cisplatin 60 mg/m 2 d1 60 mg/m 2 d1 5-FU 200 mg/m 2 200 mg/m 2 d1-21 d1-215-FU 200 mg/m 2 200 mg/m 2 d1-21 d1-21 Epirubicin 40 mg/m 2 d1 40 mg/m 2 d1 Cisplatin 50 mg/m 2 d1 50 mg/m 2 d1 5-FU 200 mg/m 2 200 mg/m 2 d1-21 d1-21

59. Randomized Trial of Adjuvant Chemoradiation After Resection of Gastric Adenocarcinoma RANDOMIZE 5-FU5-FU IVCI 5-FU LeucovorinRT Leucovorin X2 ECF5-FU IVCI ECF RT X2 540 eligible patients required to detect a 25% improvement in overall survival (alpha  0.05)

60. CALGB 80101: Worst Grade Toxicity by Treatment Arm – Updated N =387 Toxicity Arm A Mayo FU/LV Arm B ECF  Grade 3 diarrhea 16%6%  Grade 3 nausea 17%15%  Grade 3 emesis 10%11%  Grade 4 neutropenia 33%17% Any grade 4-5 event 45%23%

61. Magic Study: Perioperative ECF Cunningham et al NEJM 2006 RANDOMIZE ECF X3 N = 250 N = 253 Resectable distal esophageal and gastric adenocarcinoma ECF X3 Surgery Surgery Recruitment: July 1994-April 2002

62. MAGIC: Does Pre-op ECF Improve Resectability? 70% (166/240) 166 240 14 days Surgery alone N = 253 0.03 P 66% 166/253 0.6468%R0 rate - intent to treat 169/250R0 resection - intent to treat 79% (169/219) R0 resection rate 169 R0 resection 219 Proceeded to surgery 99 days Median time to surgery Pre-op ECF N = 250

63. MAGIC: Progression-free survival* Logrank p-value = 0.0001 Hazard Ratio = 0.66 (95% CI 0.53 - 0.81) Patients at risk CSC S 250 159 9968463223 253124574228158 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months from randomisation 0122436486072 163250 190253 EventsTotal CSC S Progression-free Survival rate *Included relapse, PD and death from any cause.

64. MAGIC: Overall survival Patients at risk Logrank p-value = 0.009 Hazard Ratio = 0.75 (95% CI 0.60 - 0.93) CSC S 25016811179523827 253155805031189 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months from randomisation 0122436486072 149250 170253 EventsTotal CSC S Survival rate

65. In operable gastric and lower oesophageal cancer, perioperative chemotherapy: significantly improves progression-free survivalsignificantly improves progression-free survival significantly improves overall survivalsignificantly improves overall survival MAGIC: Conclusions Cunningham ASCO 2005

66. Randomized Trial of Adjuvant Chemoradiation After Resection of Gastric Adenocarcinoma RANDOMIZE 5-FU5-FU IVCI 5-FU LeucovorinRT Leucovorin X2 ECF5-FU IVCI ECF RT X2 540 eligible patients required to detect a 25% improvement in overall survival (alpha  0.05)

67. Is Pre-op Therapy better than Post-op? Is MAGIC better than INT-0116?

68. MAGIC v. 0116: Patient Characteristics 27%*43% ≥ 4 pos. nodes 72%*85% Node positive 28%*15% Node negative 64%*68%T3/T4 503554 No. of Pts. MAGIC INT 0116 *Surgery alone arm Baseline pathologic characteristics:

69. MAGIC v. 0116: Two-Year Survival Surgery Alone Chemorads Or Chemo MAGIC40%48% 011652%58%

70. Absolutely not: Due to differences in patient selection and study design: Any cross-trial comparison is flawed and essentially uninterpretable MAGIC Patients with presumed resectable cancer INT 0116 Patients with R0-resected cancer

71. CALGB 80101: Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma RANDOMIZE 5-FU5-FU IVCI 5-FU LeucovorinRT Leucovorin X2 ECF5-FU IVCI ECF RT X2 540 eligible patients required to detect a 30% improvement in overall survival (alpha  0.05)

72. MAGIC-B RANDOMIZATION OperablegastricorGEJXNAdenocarcinoma ECX X 3 ECXbevacizumab ECX ECX-B Surgery Surgery Accrual: 1,100 patients

73. CRITICS STUDY RANDOMIZATION 788 patients withoperablegastriccancer ECX X 3 ECX ECX RT 45Gy/25 fx CapecitabineCisplatin Surgery Surgery

74. ONGOING AND FUTURE QUESTIONS Does ECF improve the efficacy of post-op chemorads? Does ECF improve the efficacy of post-op chemorads? What is the role of radiotherapy? What is the role of radiotherapy? Neoadjuvant vs. post-operative therapy? Neoadjuvant vs. post-operative therapy? Is ECF the optimal chemotherapy regimen? Is ECF the optimal chemotherapy regimen? Role of biologics in adjuvant therapy? Role of biologics in adjuvant therapy? Can we improve accrual to our trials? Can we improve accrual to our trials?

75. Failed Pre- and Postoperative Trials in Gastroesophageal Cancer No. of pts. accrued No. of pts. expected Trial54620INT9% 59450 Dutch Neoadjuvant 13% 278400 FFCD 8801 70% 206760EORTC27% 191480ICCG40% Percent enrolled 7882,710Total29%