1. GI Highlights ASCO 2006 George A. Fisher MD PhD Stanford University Cancer Center

2. ASCO ‘06 GI Highlights Less impressive than ‘03-05 Metastatic colon –Bevacizumab update –EGFR inhibition –Chemo vacations Pancreas –Metastatic Gem v. Fixed dose rate gemcitabine v. gemox –Adjuvant 5-FU-radiation + (5-FU vs Gem) Esophageal –Neoadjuvant CRT vs surgery alone Advanced Gastric –Alternatives to 5-FU and cisplatin Anal squamous cell –Cisplat/5-FU induction and concurrent vs. mitomycin/5-FU concurrent with radiation

3. Bevacizumab Update TREE Trial: Final Analysis (Hochster et al) –(FOLFOX vs bFOL vs CAPOX) + Bev BEAT Trial (Michael et al) – Feasibility of Metastatectomy in Bev treated patients

4. Infusional vs Bolus vs Oral Fluoropyrimidine based Therapies THE TREE TRIALS (Hochster et al #3510) Randomized Phase II Study in first line metastatic colorectal cancer –TREE 1 = FOLFOX vs bFOL vs CAPOX –TREE 2 = same plus bevacizumab

5. TREE 2 (223 patients) mFOLFOX 6 + Bev at 5 mg/kg q 2 weeks bFOL (bolus 5-FU weekly x 3 with oxali q 2 weeks) and Bev at 5 mg/kg q 2 weeks) CAPOX: with 825 mg/m 2 capecitabine d 1- 14, oxali 130/m 2 d 1 and Bev 7.5 mg/kg q 3 weeks Infusional vs Bolus vs Oral Fluoropyrimidine based Therapies THE TREE TRIALS (Hochster et al #3510)

6. Tree 2 Trial : Efficacy (Hochster et al #3510) mFOLFOX + Bev bFOL + Bev CAPOX + Bev P value Response Rate 53%41%48%ns Time to Progression 9.9 mos8.3 mos10.3 mosns Overall Survival 26.0 mos20.7 mos27.0 mosns

7. TREE 2 Trial: Conclusion CAVEAT –randomized Phase II: not powered for small differences in effect Bolus 5-FU + oxaliplatin + Bevacizumab –probably inferior with greater toxicity and trend toward lower efficacy FOLFOX + Bev vs CAPOX + Bev –“comparable” efficacy / toxicity when capecitabine dose reduced to 825 mg/m 2 bid –“equivalence” of efficacy not yet established

8. BEAT Trial: Feasibility of Metastatectomy in Patients Treated with Bevacizumab [Michael et al ASCO ‘06] 1,927 Metastatic chemo-naïve patients from 41 countries FOLFOX (37%) or FOLFIRI (28%) or CAPOX (19%) with Bev q 2 or 3 weeks 43 pts (2.4%) underwent metastatectomy –91% liver / 5% lung / 2% nodal / 2% peritoneal –57% no residual dz / 20% residual / 23% ?? –Median time from last bev dose: 67 days Protocol specified minimum of 6 weeks (42 days)

9. Results: No complications: 67% Complications: 30% –Bleeding / wound healing: 0% –Operative site infection: 12% –Gastric perf / portal vein thrombus / MI: 6% –Ascites / pleural effusion / fever / bowel obstruction: 2% each BEAT Trial: Feasibility of Metastatectomy in Patients Treated with Bevacizumab [Michael et al]

10. BEAT Trial Conclusion No significant bleeding or wound healing complications when bevacizumab held for minimum of 6 weeks before elective metastatectomy Only 2.4% (44 patients) of entire study group reported metastatectomy Michael et al (ASCO ‘06)

11. Update on EGFR Inhibition First line trials New inhibitors Efficacy in EGFR (-) patients

12. EGFR Inhibitors Antibodies: –Cetuximab –Panitumumab: Fully humanized EGFR specific Tyrosine Kinase Inhibitors –e.g. Gefitinib / Erlotinib Multi-targeted Tyrosine Kinase Inhibitors –e.g. ZD 6474 / XL647 / others…

13. First Line EGFR Inhibitors FOLFIRI vs FOLFOX + Cetuximab (CALGB 80203: Venook et al #3509) Originally randomized phase III study in first line metastatic colorectal cancer with accrual goal of 2200 pts Accrual slowed with approval of first line bevacizumab Study closed at 238 pts and redesigned as randomized Phase II trial

14. All Patients (combined FOLFIRI + FOLFOX) - Response rate: 38% vs. 52% with Cetuximab (p =.02) - Progression free and overall survival too premature to present FOLFIRI vs FOLFOX + Cetuximab (CALGB 80203: Venook et al #3509) FOLFIRI + Cetux FOLFOXFOLFOX + Cetux Response rate 36%44%40%60%

15. Difficult to complete Phase III trials when “standard of care” changes Usual caveat of randomized Phase II comparisons (small numbers) Activity of EGFR inhibitors in first line chemotherapy supported Underscores importance of current national Phase III first line trial FOLFIRI vs FOLFOX + Cetuximab CALBGB 80203: Conclusions

16. Cooperative Group Trial for Metastatic Colorectal Cancer RANDOMIZATIONRANDOMIZATION Investigator’s Choice: mFOLFOX6 or FOLFIRI + Bevacizumab + Cetuximab + Bevacizumab + Cetuximab

17. Panitumumab in Metastatic Colorectal Cancer Patients with documented progression on irinotecan and oxaliplatin regimens Panitumumab 6 mg/kg q 2wk vs BSC Response rate 8%; median duration 4.2 mos PanitumumabBSC # patients231232 2 month PFS49%30% 4 month PFS18% 5% Peters M. et al AACR 2006

18. Efficacy of EGFR Inhibitors: No Correlation with EGFR Expression (Hecht # 3547 ASCO ‘06) Multicenter phase II study of panitumumab Metastatic colorectal cancer with disease progression after oxali and irinotecan regimens EGFR membrane staining in <1% or 1-9% of evaluated tumor cells by IHC Interim analysis of 23 patients presented

19. Panitumumab Efficacy in low or no EGFR expressing tumors *< 1%*1-9%**>10% Number of Patients 11839 Response Rate 2 (18%) 1 (8%) 3 (8%) Stable Disease 4 (36%) 3 (25%) 8 (21%) *Hecht et al #3547 **Berlin et al #3548

20. Chemotherapy Free Intervals When Less is More OPTIMOX Trials: (“optimal use of oxaliplatin”) –minimizing oxaliplatin neurotoxicity –testing the idea of a “chemotherapy vacation” Alternating Therapy: (2 months on - 2 months off) –decreasing the dose density of FOLFIRI Entry criteria for both studies: “unresectable” metastatic disease

21. OPTIMOX Trial Designs (Maindrault-Goebel et al #3504) OPTIMOX 1 OPTIMOX 2 FOLFOX 4 until “treatment failure” FOLFOX 7 for 6 cycles LV5FU2 Until progression FOLFOX 7 mFOLFOX 7 for 6 cycles *Observation Until progression FOLFOX 7 R R mFOLFOX 7 for 6 cycles LV5FU2 Until progression FOLFOX 7

22. OPTIMOX-Trials: DDC t T size FOLFOX PFS 1 PD Baseline progression PFS 2 Progression at reintroduction DDC=PFS1+PFS2 Tournigand JCO 2006 ?

23. OPTIMOX Results (Maindrault-Goebel et al #3504) OPTIMOX 1OPTIMOX 2 # patients100102 Response rate61% Reintroduction of oxaliplatin 32%52% Response rate to second oxaliplatin 13%31% Progression Free Survival (PFS) 8.7 mos6.9 mos (p <.05) Duration Disease Control (PFS1+PFS2) 12.9 mos11.7 mos (p =.4)

24. Median chemo free intervals: –Non-responders (SD): 3.9 mos –Responders: 5.1 mos –Overall: 4.6 mos –*favorable patients: 8.0 mos OPTIMOX Subset Analysis (Maindrault-Goebel et al #3504) *performance status, 1 site of metastatic disease, LDH and Alkaline Phos < 3x upper limit of normal

25. OPTIMOX Conclusions Presumed quality of life advantage associated with median ~5 month chemo vacation may offset diminished progression free survival Next study will include targeted therapy administered as maintenance during chemo free interval

26. Alternating vs. Continuous FOLFIRI in Metastatic Colorectal Cancer (Labianca et al #3505) Study Schema 337 patients randomized FOLFIRI Q 2 weeks X 2 mos FOLFIRI q 2 weeks until treatment failure Chemo Vacation X 2 mos FOLFIRI Q 2 weeks X 2 mos etc.

27. Alternating vs. Continuous FOLFIRI in Metastatic Colorectal Cancer (Labianca et al #3505) IntermittentContinuous Response rate33.6%36.5% Progression Free Survival (PFS) 6.2 mos*6.5 mos Overall Survival16.9 mos*17.6 mos 2nd line therapy56%55% Median # cycles88 * Hazard Ratio = 1.0

28. Studies of Chemotherapy Free Intervals: Conclusions Diminishing dose density does not appear to impact duration of disease control Presumption of improved quality of life New trials need to confirm and extend these observations incorporating targeted therapies

29. Celecoxib: No Benefit [FOLFIRI vs IFL vs CAPIRI] + celecoxib (Fuchs et al #3506 ASCO ‘06) –The death of IFL (?) Inferior efficacy with higher toxicity –Caution with capecitabine substitutions Dose reductions necessary in combination regimens [FOLFIRI vs CAPIRI] + celecoxib (De Greve et al #3577 ASCO ‘06) –Another Phase III trial suspended early –Chemo + celecoxib vs chemo + placebo response rates 26 vs 46% favoring placebo…??

30. Where to Go from Here… New targets / new agents –Death pathway agonists –mTOR inhibitors Molecular predictors of response –EGFR activation (?) –VEGF polymorphisms –LDH (?) Combining targeted therapies

31. Where to Go from Here… Novel trial designs to incorporate chemo-free intervals Identifying who among metastatic colon cancer patients can be “cured” –Aggressive multidrug therapy with resection / ablations for the potentially curable –Chemo-free intervals to prolong quality living during disease control

32. And finally, extending successes beyond metastatic disease Incorporating targeted therapy into multimodality care of rectal cancer Improving cure rates in early stage II/III Applying gains to other tumor sites Finding a way to pay for it all… CapOxIriBevacizutux = ~$$$ / month

33. Metastatic disease –ECOG 6201: fixed dose rate gemcitabine vs FDR gem + oxaliplatin vs standard gem Adjuvant therapy –RTOG 9704: Gem x 3 wks - 5-FU / radiation - gem x 3 mos 5-FU x 3 wks - 5-FU / radiation - 5-FU x 3 mos ASCO ‘06: Pancreas Cancer

34. Phase III Study in Advanced Disease ECOG 6201 (Poplin ASCO ‘06: #LBA4004) “standard” gemcitabine (1000 mg/m 2 over 30 min) Fixed Dose Rate gemcitabine (1500 mg/m 2 at 10 mg/m 2 /min [150 minutes] Gemcitabine (FDR) + oxaliplatin q 2 wks Gemcitabine (1000 mg/m 2 over 100 min) day 1 Oxaliplatin (100 mg/m 2 over 2 hours) day 2

35. E6201: Gem vs FDR Gem vs FDR Gem + Oxaliplatin Patients: –12% Performance status 2 –12% with locally advanced (88% mets) –Medium f/u 12.2 months Statistics –Goal: improvement in median survival from 6 mos (control gem) to 8 mos in either experimental arm (p<.025 and 81% power) [Poplin et al ASCO ‘06]

36. Gem vs FDR Gem vs FDR Gem + Oxaliplatin: Results GemFDR GemFDR Gem + Ox # patients279277276 *Progression49%51%40% *Toxicity15%20%24% Response5%10%9% Median OS4.9 mos6.0 mos5.1 mos 1 yr survival17%21% [Poplin et al ASCO ‘06] *reasons cited to go off study

37. Hazard ratio of FDR Gem vs Gem –HR =.83 (.69 -1.0) p =.05 Hazard ration of FDR Gem + Ox vs Gem –HR =.88 (.73 - 1.05) p =.16 Conclusion: Single agent Gemcitabine remains standard of care in metastatic pancreas cancer Caveat: ?? role for FDR gem or gem + platinum analogue when response rate is clinically important (offset by increase in cytopenia / N / V / neuropathy) Gem vs FDR Gem vs FDR Gem + Oxaliplatin: Results

38. Phase III Trial in Resected Pancreas Cancer: RTOG 904 –492 pts stratified by nodes / margins / tumor size ( 3 cm) Gem x 3 wks - 5-FU / radiation - gem x 3 mos 5-FU x 3 wks - 5-FU / radiation - 5-FU x 3 mos –Primary endpoint overall survival Pancreatic head only (86% of patients) All patients –Slight imbalance in study arms T3/4 disease: 81% in gem arm; 70% in 5-FU (p=.06)

39. RTOG 9704: Head of Pancreas Tumors Only

40. RTOG 9704: All Patients

41. RTOG 9704: Conclusions Addition of gemcitabine to post-op radiation / 5-FU improves survival in tumors of the pancreatic head Reason for lack of statistical benefit for entire group unclear Role of radiation remains controversial and not addressed in this study

42. ASCO ‘06 Esophageal Cancer Tepper et al #4012 CALGB 9781 Phase III planned 500 patients with resectable esophageal ca –Chemoradiation f/b surgery vs surgery alone Chemo (cisplat 100/m 2 + 5-FU 1000/m 2 d1-4) Chemo on weeks 1 and 5 with radiation –Trial closed early due to poor accural –Results of 56 patients reported

43. Trimodality Therapy vs Surgery Alone for Esophageal Cancer (Tepper et al #4012 ASCO ’06) Primary endpoint: overall survival –Expected surgery control arm: 20% –Goal: 40% increase in 5 year OS –Median follow-up 6 years CRT f/b Surgery Surgery aloneP value Median OS4.5 yrs1.8 yrs=.02 5 yr OS39%16%<.008

44. Trimodality Therapy vs. Surgery Alone in Esophageal Cancer: Conclusions Poor accrual limits statistical power; yet magnitude of difference statistically significant despite small numbers Many questions still unanswered –Accuracy of clinical staging –Selection criteria for surgery candidates –Role of newer agents

45. ASCO ‘06: Gastric Cancer Two Phase III trials in metastatic disease 5-FU/cisplatin vs. mFOLFOX6 – (Al-Batran et al #LBA4016) Epirubicin + (cisplatin vs oxaliplatin) + (5-FU vs capecitibine) – (Cunningham et al #LBA4017)

46. Metastatic Gastric Cancer FLP (cisplatin) vs. FLO (oxaliplatin) FLP: 5-FU 2000/m 2 (24 hr CI) q wk leucovorin 200/m 2 q wk cisplatin 50/m 2 q 2 wks FLO:5-FU 2600/m 2 (24 hr CI) q 2 wks leucovorin 200/m 2 q 2 wks oxaliplatin 85/m 2 q 2 wks Statistical Goal: Improve TTP from 3.6 to 5.1 months [Al-Batran #LBA4016]

47. FLP vs. FLO in Gastric Cancer (# patients)FLP (112)FLO (108) Median time on therapy3.0 mos4.3 mos Response25%34% Time to Progression3.8 mos*5.7 mos Time to Treatment Failure3.1 mos*5.3 mos [Al-Batran ASCO ‘06: #LBA4016] *statistically significant

48. Phase III Gastric Trial: Comparing capecitabine with 5-FU and oxaliplatin with cisplatin (Cunningham #LBA4017) Bifactorial design with all patients receiving epirubicin (50/m 2 q 3 wks) Randomized to capecitabine 625/m 2 b.I.d. continuously vs. 5-FU 200/m 2 daily by continuous infusion Second randomization to oxaliplatin (130/m 2 ) or cisplatin (60/m 2 ) q 3 weeks Four arms: ECF / ECX / EOF / EOX Primary endpoint: non-inferiority in overall survival (cap vs 5-FU / ox vs cisplatin)

49. Phase III Gastric Trial: capecitabine (X) vs 5-FU and oxaliplatin vs cisplatin (Cunningham #LBA4017) ECFECXEOFEOX # patients263250245244 Median # cycles6666 Response41%46%42%48% 1 yr survival39.4%44.6%43.9%40.1% Hazard ratio: FU vs Xeloda (0.86); Oxali vs cisplatin (0.92) ns

50. ASCO ‘06: Randomized Gastric Trial Conclusions Oxaliplatin may be substituted for cisplatin in metastatic gastric cancer –Improved outcomes in one study –Non-inferior outcome in other –Less toxicity in both Capecitabine may be substituted for infusional 5-FU Treatment choices may be made based on toxicity / convenience

51. ASCO ‘06: Phase III Trial in Anal Cancer RTOG 98-11 [Ajani #4009] 682 patients (598 evaluable to date) –5-FU 1000/m 2 daily CI x 4 days + mitomycin 10/m 2 week 1 and 4 of radiation –5-FU 1000/m 2 daily CI x 4 days + Cisplatin 75/m 2 q 4 wks starting 2 months prior to radiation –Primary objective: improve DFS @ 5 yrs from 63% to 73% or decrease HR by 33%

52. Phase III Trial in Anal Cancer [Ajani #4009]

53. ASCO ‘06 GI Highlights Conclusions Prospective incorporation of chemo holidays –concept of “duration of disease control” Phase III studies closed early –When the “standard of care” is a moving target Capecitabine v 5-FU; oxali v cisplatin –Picking your poisons… Dilemmas in Phase III Interpretations –Statistical vs clinical significance Second generation targeted therapies in GI cancers –Phase II ASCO ‘07 / ‘08