1. Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic and Hepatocellular

2. 2007-2008 Lower Gastrointestinal Overview: Practice Implications GIST, Neuroendocrine, and Bile Duct Tumors John L. Marshall, MD Chief, Division Hematology and Oncology Georgetown University Lombardi Comprehensive Cancer Center Washington DC

3. Increased dose of imatinib has been used in progressive disease Established role for sunitinib in progressive disease setting Median time to recurrence of primary high-risk GIST is ~ 2 years Risk of recurrence in primary low-risk GIST is ~2% 2 Role of adjuvant treatment yet to be confirmed GIST: Summary of Current Treatment Options 1 Surgical resection Resectable lesions Surgery ± Imatinib Marginally resectable Imatinib Advanced, unresectable, or metastatic Imatinib currently considered standard of care for 1 st line treatment Disease progression on imatinib Increase dose of imatinib or sunitinb or clinical trial Intolerant to imatinib sunitinib Established role for sunitinib in patients intolerant to imatinib Role of treatment in neoadjuvant setting has become more clearly established 1. Adapted from the NCCN Soft Tissue Sarcoma Clinical Practice Guidelines in Oncology (Version V.3.2006). © 2006 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed December 21, 2006. To view the most recent and complete version of the guideline, go online to www.nccn.org. 2. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Cancer. 2005;103:821-829.www.nccn.org

4. GIST: Many Outstanding Questions Dose Duration Adjuvant therapy Genotypes and Patient selection New Agents

5. Dose Consort –Blanke, C. D. et al. J Clin Oncol; 26:626-632 2008 B2222 Study Group –Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008 Demetri, von Mehren et al –GI ASCO and ASCO 2008

6. Blanke, C. D. et al. J Clin Oncol; 26:626-632 2008 Fig 2. Progression-free survival

7. Blanke, C. D. et al. J Clin Oncol; 26:626-632 2008 Fig 3. Overall survival

8. B2222 Study Group Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher- Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing KIT Charles D. Blanke, George D. Demetri, Margaret von Mehren, Michael C. Heinrich, Burton Eisenberg, Jonathan A. Fletcher, Christopher L. Corless, Christopher D.M. Fletcher, Peter J. Roberts, Daniela Heinz, Elisabeth Wehre, Zariana Nikolova, Heikki Joensuu JCO 2008

10. Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008 Fig 1. Time to progression

11. Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008 Fig 2. Overall survival

12. GI ASCO 2008:3

14. Update ASCO 2008 J Clin Oncol 26: 2008 (May 20 suppl; abstr 4523) M. von Mehren, Y. Wang, H. Joensuu, C. D. Blanke, E. Wehrle, G. D. Demetri OOR was achieved by –8 of 18 (44%) pts in Q1 (Cmin <1,110 ng/mL) –24 of 36 (67%) Q2 (>1,110 - <2,040 ng/mL) –14 of 19 (74%) Q3 and Q4 (>2,040 ng/mL) In pts with GIST with exon 11 KIT mutation (n=39), –OOR was 55.6% for Q1 vs 93.3% for Q2-Q4 (p=0.006). Exposure to adequate drug levels of IM appears to correlate with clinical benefit; pts with the lowest IM levels show the lowest OOR and shortest TTP. These results suggest that monitoring IM exposure may be important for optimal clinical outcome.

15. Duration: Imatinib Interruptus Blay, J.-Y. et al. J Clin Oncol; 25:1107- 1113 2007 –After one year Perol ASCO 2008 –Rescue after one year Adenis ASCO 2008 –After 3 years

16. Blay, J.-Y. et al. J Clin Oncol; 25:1107-1113 2007 Fig 1. Description of randomly and nonrandomly assigned GI stromal tumor (GIST) patients

17. Blay, J.-Y. et al. J Clin Oncol; 25:1107-1113 2007 Fig 2. (A) Progression-free survival (PFS) in randomly assigned patients, (B) overall survival (OS) in the continuous (CONT) and interrupted (INT) arms, and (C) imatinib-resistant PFS in the CONT and INT arms

18. Duration: Imatinib Interruptus 1 Year D. Pérol et al: J Clin Oncol 26: 2008 (May 20 suppl; abstr 10556) Despite a significant increase of PD in the I arm, IM re-introduction at the same dose allows a tumor control in the majority of pts. IM interruption seems to have no impact on the sensitivity/resistance of GIST tumor cells.

19. Duration: Imatinib Interruptus 3 Years A. Adenis et al: J Clin Oncol 26: 2008 (May 20 suppl; abstr 10522) After 3 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM, 50 non-progressive pts. 1 yr PFS were 87.7 and 23.7% for C and I arms, respectively. IM reintroduction 100% disease control so far. OS were similar in both arms No impact of IM discontinuation on OS could be detected. This work is supported by research funding from Novartis Pharma.

20. Adjuvant Treat ‘em now or Treat ‘em later DeMatteo ASCO 2007 ACOSOG Z9001 EORTC 62024 Ph III SSG XVIII/AIO

21. DeMatteo ASCO 2007

24. 24 Recurrence Gleevec 800mg x 2 yrs ACOSOG Phase III Trial: Adjuvant Imatinib in Patients with High Risk Primary GIST ACOSOG Z9001: randomized, double-blind study of adjuvant Imatinib vs placebo post resection of primary GIST 10 years or until death Primary Kit + GIST (≥ 3 cm) Placebo x 1 year Gleevec 400mg x 1 year FOLLOWFOLLOW Complete Gross Resection 14-70 days prior American College of Surgeons Oncology Group. Sarcoma Organ Site Committee. Available at: http://www.acosog.org/studies/synopses/Z9001_Synopsis.pdf. Gleevec 400mg x 2 yrs Recurrence Primary Objective: Recurrence Free Survival (RFS)

30. 30 Ph III Adjuvant Trial (EORTC 62024) *Due to progression or unacceptable toxicity. Available at: http://clinicaltrials.gov/ct/show/NCT00103168. Follow for 5 years No treatment Imatinib (400 mg/d for 2 years) Complete resection of GIST Discontinued treatment*

31. 31 Ph III SSG XVIII/AIO Trial of Adjuvant Imatinib in Patients with GIST 12 months versus 36 months duration of adjuvant treatment with Imatinib for operable GIST with high risk for recurrence Observation period: Median 5 years from randomization Available at: http://clinicaltrials.gov/ct/show/NCT00116935. N=345 Patients with high or very high risk GIST

32. 32 Genotypes, Surrogates and Tumor Resistance We could be even smarter Tumor Based Patient Selection –Bad News from the start KIT Exon 9 PDGFRA D842V WT KIT/PDGFRA Genotypes –Acquired Mutations occur during treatment Soluble KIT –Early Predictor?

33. 33 Time to Development of Acquired Resistance to Imatinib varies with site of KIT Gene Mutation Primary Therapy of Metastatic GIST Exon 11 576 days Exon 9 308 days No mutation 251 days p=0.003 p=0.007 Heinrich, et al. ASCO Plenary 2005

34. 34 Genotype Median Survival Exon 11Not reached Exon 91347 days (192 wks) No mutation250 days (36 wks) Imatinib: Overall Survival by Genotype Blanke CD, et al. J Clin Oncol. 2006;24(Suppl):9528. Exon 11 Exon 9 No Mutation 0250500750100012501500 0 10 20 30 40 50 60 70 80 90 100 P-value = 0.0012 Days Overall Survival (%) Survival Number at Risk Days025050075010001250 Exon 11868281736453 Exon 9232218141111 No Mutation953333

35. 35

36. 36 Blackstein et al ASCO 2007 and GI ASCO 2008

37. 37 (SUTENT: placebo) Placebo (n = 118) SUTENT (n = 243) 50 mg/day, 4 weeks on, 2 weeks off Imatinib refractory or intolerant GIST patients Conducted at 56 sites in Europe, USA, Australia, and Asia (Singapore) Randomization 2:1 Placebo 4 weeks on, 2 weeks off Cross over to SUTENT at progression Continue as long as clinical benefit Phase III Trial of SUTENT in Imatinib Resistant/Intolerant GIST SUTENT Casali PG, et al. J Clin Oncol. 2006;24(Suppl):9531 (Abstract). *First interim analysis January 2005 *Second interim analysis, April 2006

38. 38

39. 39 Blackstein et al ASCO 2007 and GI ASCO 2008

40. Sorafenib in GIST L. Wiebe, J Clin Oncol 26: 2008 (May 20 suppl; abstr 10502) Progression after both IM and SU 26 pts (6 IM-RES, 20 IM/SU-RES) enrolled 1/06-12/07 at 5 sites. Disease control rate (PR + SD): 71%. These preliminary data suggest that SOR is active and well-tolerated in pts with IM-and SU-resistant GIST. Supported by NCI grant N01-CM-62201.

41. IPI-504 Hsp90 inhibitor in GIST A. J. Wagner et al: J Clin Oncol 26: 2008 (May 20 suppl; abstr 10503) Inhibition of the Hsp90 chaperone protein results in selective destruction of the mutated KIT kinase in human GIST cell lines across multiple genotypes which confer TKI resistance. 54 pts (38 GIST; 16 STS) 5 dose levels (90 mg/m2 IPI-504 [n=6], 150 [6], 225 [9], 300 [3], 400 [23] 500 [7]). 18 GIST pts assessed by PET, 22% had a PET partial response and an additional 66% had stable disease according to the EORTC PET response criteria.

42. Fun Facts about Neuroendocrine Cancers Carcinoids are different from Pancreatic Neuroendocrine Cancers There is an increasing incidence of non- functional pancreatic NETs, at least in Michigan (Fitzgerald et al GI ASCO 2007) Streptozotocin/5FU did not beat depot Octreotide for TTP and was more toxic in Pancreatic NETs (Pavel et al GI ASCO 2008)

43. New Agents in Neuroendocrine Tumors Angiogenesis –Bevacizumab (Kulke et al GI ASCO 2008) –PTK787 (Anthony et al ASCO 2007, GI ASCO 2008) –Sorafenib (Hobday et al ASCO 2007) Somatostatin Analogues –Safety of high doses (Chadha et al GI ASCO 2008) –Radiolabelled Octreotide analogues –Pasireotide (SOM230) (Kvols et al ASCO 2007) Chemotherapy –FOLFOX + Bevacizumab (Bergsland et al GI ASCO 2008) –CAPOX + Bevacizumab (Kunz et al GI ASCO 2008) –Pemetrexed (negative) (Bhargava et al ASCO 2007) –Everolimus (Rad001) (Yao et al ASCO 2007) –Temozolomide (Kulke et al ASCO 2007)

44. Efficacy of VEGF Inhibitors in NETs DrugMOANRR (%)Other Endpoints bevacizumab 1 VEGF18 Carc17% sunitinib 2 VEGF, PDGF, c-Kit, RET 41 Carc 61 Islet 2 15 TTP, wks: 42 33 sorafenib 3 VEGFR-2, VEGFR-3, PDGFR- ϐ, Raf-1, B-Raf, 51 Carc 42 Islet 7 11 Progression Free at 6 mos: Carc 58% Islet 72% 1 Yao et al, Proc ASCO, 2005, A4007 2 Kulke et al, Proc ASCO, 2005, A4008 3 Hobday et al, Proc ASCO, 2007, A4504

45. Yao, J. C. et al. J Clin Oncol; 26:1316-1323 2008 Fig 3. Progression-free survival (PFS) estimates using the Kaplan-Meier method Depot Octreotide + (Bevacizumab vs/+ PEG INF) in Carcinoid

46. Somatostatin Receptor-Targeted Radionucleotide Therapy Why is this not the current standard?  [ 111 In-DTPA] Octreotide (Emits low energy “Auger” electrons; effective only at short distances)  [ 90 Y-DOTA, Tyr 3 ] Octreotide (high energy B- particle emitter)  [ 177 Lu-DOTA, Tyr 3 ] Octreotide (low energy B- particle emitter)

47. Tumor Type Total No.of Patients Complete Remission Partial Remission Minor Response Stable Disease Progressive Disease Carcinoid 66 – 13 (20%) 28 (42%)12 (18%) NE Pancreas 32 3 (9%) 7 (22%) 11 (34%)4 (13%) NE Unknown Origin 17 –6 (35%)2 (12%)4 (24%)5 (29%) Gastrinoma 8 –5 (63%)2 (25%)1 (12%) – Insulinoma 2 –1 (50%)–– Total 125 3 (2%)32 (26%)24 (19%)44 (35%)22 (18%) Tumor Responses in 125 Patients 3 Months After the Last Administration of 177Lu-Octreotate Sun, W. et al. J Clin Oncol; 23: 4897-4904 2005

48. Longterm outcome of peptide receptor radionuclide therapy (PRRT) in 454 patients with progressive neuroendocrine tumors using yttrium-90 and lutetium-177 labelled somatostatin receptor targeting peptides. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4517) D. Hörsch, V. Prasad, R. P. Baum Yttrium-90 (Y-90)- and/or lutetium-177 (Lu-177) DOTA-TATE (Lu-TATE) 454 pts. Low toxicity, little renal toxicity. Objective tumor responses (including improvement of clinical symptoms) were seen in 88/93% of the patients. Conclusions: The stuff works and is well tolerated.

49. Temozolomide-Based Therapy in NET: Efficacy Combined Analysis (76 Pts) Tumor TypeN Response (RECIST) Pancreatic NET 3511 (31%) Carcinoid 380 Pheo/Paraganglioma 31 (33%) Kulke et al, Proc ASCO 2007

50. Bile Duct Tumors, Cholangiocarcinomas  The Unknowns –Should we use radiation? –Is there a role for orthotopic liver transplantation? –Is there a standard chemotherapy?

51. Bile Duct Tumors, Cholangiocarcinomas Role of Radiation  No randomized trials, lots of bias  SEER Database analysis of 8,597 patients –All had surgery, 20% had radiation –Overall Survival Radiation- 16 months No Radiation- 9 months –Conclusion: Radiation should be strongly considered. –Shinohara et al: GI Cancers Symposium:143, 2008  Small Retrospective Analysis –45 patients- resected then chemo/radiation –5 year OS 33%, 5 year local control 78% –Radiation helped local control –Conclusion Systemic mets still the major problem, need better drugs –Nelson et al: GI Cancers Symposium:150, 2008

52. Bile Duct Tumors, Cholangiocarcinomas Role of Liver Transplant  Mayo Clinic Series –Early stage Cholagio or Cholagio in PSC. –Neoadjuvant chemo and radiation –Operative staging to rule out LN involvement –Orthotopic liver transplant –90 of 148 went to transplant –57% 5 year OS –74% 5 year OS in those transplanted –Blechacz et al: GI Cancers Symposium:139, 2008  This is not translatable to general practice

53. Bile Duct Tumors, Cholangiocarcinomas Any New Chemo Options?  Gemcitabine/Carboplatin Phase II (49 patients) –29.2% PR, 50% SD –Acceptable toxicity –Suresh et al: Proc Am Assoc Clin Oncol 15102, 2007  Sorafenib Phase II (36 patients) –6% PR, 29% SD, Median PFS 2 months –Low response, maybe similar SD rates as chemo? –El-Khoueiry et al: Proc Am Soc Clin Oncol 4639, 2007  Plenty of room for improvement

54. Sorafenib: ASCO 2008  Abstract No: 4590  J Clin Oncol 26: 2008 (May 20 suppl; abstr 4590)  C. Dealis, F. Bertolini, N. Malavasi, S. Zironi, C. Boni, M. Banzi, E. Aitini, G. Cavazzini, G. Luppi, P. F. Conte  Biomarkers were also assessed at baseline by IHC: VEGFr, pRaf-1, pMEK, pERK. SOR was administered at the dose of 400 mg PO, BID, continuously.  46 pts were enrolled  Tumor response 1 PR (4%), 12 SD (50%), 11 PD (46%);  DC was reported in 31.7% of pts  54% of the pts treated for at least 12 weeks achieved a SD or PR.  Biomarker expression in relation to treatment outcome will be available for the meeting.

55. GEM/OX/CETUXIMAB: ASCO 2008  Abstract No: 4586  J Clin Oncol 26: 2008 (May 20 suppl; abstr 4586)  B. Gruenberger, J. Schueller, K. Kaczirek, M. Bergmann, W. Klose, M. Bischof, G. Schernthaner, T. Gruenberger  Single-centre phase II study of cetuximab in combination with gemcitabine and oxaliplatin  Cetuximab 500 mg/m² on day 1 followed by 1,000mg/m² gemcitabine (day 1) and 100mg/m² oxaliplatin on day 2 were administered every second week.  22 patients (11 male, 11 female)  ORR 58%, 1 CR, 6 SD  Cetuximab in combination with gemcitabine and oxaliplatin seems a well tolerated regimen in patients with cholangiocarcinoma. The first results demonstrate promising efficacy for both response rates and progression-free survival. Therefore cetuximab in combination with GEMOX deserves further evaluation in prospective randomized trials.

56. Bile Duct Tumors, Cholangiocarcinomas  The Unknowns –Should we use radiation? Probably –Is there a role for orthotopic liver transplantation? In some patients –Is there a standard chemotherapy? No