1. Please note, these are the actual video- recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

2. Year in Review 2012 Non-CRC GI Cancers Bert H O’Neil, MD Associate Professor Director, GI Oncology Clinical Research Program Medical Director, UNC Cancer Clinical Trials Protocol Office UNC Lineberger Comprehensive Cancer Center October 27, 2012 Orlando, Florida

3. A 60-year-old patient is S/P removal of a 4-cm jejunal tumor that is found to be a GIST. 3 mitoses/HPF (5-year risk of relapse = 24%). Would you likely recommend adjuvant imatinib? N = 71

4. One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor: A Randomized Trial Joensuu H et al. JAMA 2012;307:1265-72. ASCO Plenary 2011

5. Imatinib for 12 months An open-label Phase III study Imatinib for 36 months Follow-up SSGXVIII: Study Design R Joensuu H et al. Proc ASCO 2011;Abstract LBA1. 1:1 Eligibility: High recurrence risk (tumor diameter >10 cm or mitosis count >10/50 HPF or size >5 cm and mitosis count >5/50 HPF or tumor rupture spontaneously or at surgery) Stratification: 1) R0 resection, no tumor rupture and 2) R1 resection or tumor rupture

6. SSGXVIII: RFS in Efficacy Population* *Excluded: Consent withdrawn, no GIST at pathology review or overt metastases at study entry Joensuu H et al. JAMA 2012;307:1265-72. Imatinib 12 months Imatinib 36 months Hazard ratiop-value 3-y RFS 62.1% 88.1%0.46<.001

7. Imatinib 12 months Imatinib 36 months Hazard ratiop-value 5-y OS 81.7% 92.0%0.450.02 SSGXVIII: Overall Survival (ITT) Joensuu H et al. JAMA 2012;307:1265-72.

8. Optimal Duration of Adjuvant Therapy for Patients with Resected Gastrointestinal Stromal Tumors Blanke CD et al. JAMA 2012;307(12):1312-4.

9. Editorial: Issues Remaining from SSGXVIII Are patients cured or indefinitely in remission? Should we treat post-operative patients longer than 3 years? –Should we treat life long? How do we study biologics in the adjuvant setting? Will patients take biologics long-term post-operatively? What recurrence risk “mandates” treatment in a perfect world? –Most US experts use ~25% Blanke CD et al. JAMA 2012;307(12):1312-4.

10. Efficacy and Safety of Regorafenib in Patients with Metastatic and/or Unresectable GI Stromal Tumor After Failure of Imatinib and Sunitinib: A Multicenter Phase II Trial George S et al. J Clin Oncol 2012; 30(19):2401-7.

11. Randomized Phase III Trial of Regorafenib in Patients with Metastatic and/or Unresectable GIST Progressing Despite Prior Treatment with at Least Imatinib and Sunitinib: GRID Trial Demetri GD et al. Proc ASCO 2012; LBA 10008.

12. GRID Phase III: Disease Control and Overall Response Rates Objective response rate6 (4.5)1 (1.5) Complete response0 (0.0) Partial response6 (4.5)1 (1.5) Stable disease (at any time) 95 (71.4)22 (33.3) Progressive disease28 (21.1)42 (63.6) Responses based on modified RECIST v1.1 Regorafenib (N = 133) n (%) Placebo (N = 66) n (%) Disease control rate CR + PR + durable SD (≥12wks) 70 (52.6)6 (9.1) Demetri GD et al. Proc ASCO 2012;Abstract LBA 10008.

13. GRID Study: Progression-Free Survival Demetri GD et al. Proc ASCO 2012;Abstract LBA 10008. Regorafenib, N = 133Placebo, N = 66 Median PFS4.8 months0.9 months Number of events81 (60.9%)63 (95.5%) Hazard ratio: 0.27 1-sided p-value: <0.0001

14. GRID Study: Overall Survival Demetri GD et al. Proc ASCO 2012;Abstract LBA 10008. Regorafenib, N = 133Placebo, N = 66 Median OSNot reached Number of events29 (21.8%)17 (25.6%) Hazard ratio: 0.77 1-sided p-value: 0.199

15. Drug-Related Treatment-Emergent Adverse Events in ≥10% of Patients During Double-Blind Treatment Regorafenib (N = 132), % Median 23 wks exposure Placebo (N = 66), % Median 7 wks exposure Grade All345 345 Hand-foot skin reaction56.119.70015.21.500 Hypertension48.522.70.8016.73.000 Diarrhea40.95.3007.6000 Fatigue38.62.30027.31.50 Mucositis, oral37.91.5009.11.500 Alopecia23.51.5003.0000 Hoarseness22.00004.5000 Anorexia20.50007.6000 Rash, maculopapular18.23.000 000 Nausea15.90.8009.11.500 Constipation15.20.8007.6000 Myalgia13.60.8009.1000 Voice alteration11.40003.0000 Demetri GD et al. Proc ASCO 2012;Abstract LBA 10008.

16. Phase II GI 148: Study of the Hsp90 Inhibitor AUY922 for the Treatment of Refractory GIST Eligibility: Patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) who experienced progression on, are intolerant to or are not candidates for imatinib or sunitinib AUY922: An isoxazole-based compound that competitively inhibits the ATPase activity of heat shock protein 90 (Hsp90) Select Noncolorectal GI Cancer Trials

17. Would you use sorafenib for a patient with Child-Pugh B cirrhosis and metastatic hepatocellular carcinoma? N = 71

18. Second Interim Analysis of the Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib (GIDEON): Sorafenib Dosing and Safety in US Patients El-Khoueiry AB et al. GI Cancers Symposium 2012;Abstract 302.

19. GIDEON: Background/Methods/Conclusions Sorafenib first agent to improve survival in advanced HCC This is a US analysis in 326 pts from “real world” observational study –Largest prospective study ever in unresectable HCC US pts higher chance of starting on 400 mg/d versus 800 mg/d US pts more likely to get dose mod or dose interruption, despite same % drug-related adverse events But duration of sorafenib was similar in both populations “Use clinical judgment” El-Khoueiry AB et al. GI Cancers Symposium 2012;Abstract 302.

20. Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1,500 Patients: Clinical Findings in Patients with Liver Dysfunction Marrero JA et al. Proc ASCO 2011;Abstract 4001.

21. Overview of Key Data Child-Pugh A (n = 957) Child-Pugh B (n = 367) Dosing and Duration of Sorafenib Mean daily dose, mg 2 631633 Dose interruption24%22% Dose reduction37%27% Median duration of sorafenib14 weeks9 weeks Adverse Events Grade 3/4 drug-related AEs24%22% Serious AEs29%56% Efficacy Overall survival (n = 984, 376)10.3 months4.8 months Time-to-progression (n = 984, 376)4.2 months3.6 months Marrero JA et al. Proc ASCO 2011;Abstract 4001.

22. ECOG 1208: Chemoembolization with or without Sorafenib Tosylate in Treating Patients with Liver Cancer That Cannot Be Removed by Surgery ECOG/ACRIN Cooperative Group Trial www.clinicaltrials.gov, October 2012

23. E1208: Rationale and Methodology Sorafenib and TACE both work in HCC, by different methods Phase III double-blind placebo-controlled trial: TACE (cisplatin, mito, doxo) x 4 +/- sorafenib in unresectable HCC Eligibility: incurable HCC, PS ≤ 1 Primary objective: PFS Secondary objectives: OS, toxicity, patterns of failure, etc. ~76 study locations www.clinicaltrials.gov, October 2012

24. A Multicenter, Randomized, Double-Blind, Phase III Study of Ramucirumab (IMC-1121B) and Best Supportive Care versus Placebo and BSC as Second-Line Treatment in Patients with HCC Following First-Line Therapy with Sorafenib Zhu AX et al. Proc ASCO 2012;Abstract TPS4146. Trial in Progress

25. Study Rationale Blockade of VEGF improves survival in HCC, pre-clinically and clinically (sorafenib) RAM = fully human MoAb to VEGFR2 Phase II RAM study: disease control 70%, TTP 4.2 mo, OS 12 mo Zhu AX et al. Proc ASCO 2012;Abstract TPS4146.

26. Phase III Methodology Eligibility: –HCC, progression on or intolerance to sorafenib –Child-Pugh A, B7 or B8, PS ≤ 1 Treatment: RAM 8 mg/kg q2 weeks versus placebo, forever Primary objective: OS (powered to detect 6 to 8 mo) Secondary objectives: PFS, ORR, QOL, safety, PK, RAM immunogenicity Reviewed twice by DSMB and study continued Zhu AX et al. Proc ASCO 2012;Abstract TPS4146.

27. ESMO 2012 – non CRC SEARCH: Phase III trial of sorafenib plus erlotinib or placebo in patients with HCC. Zhu AX et al. Abstract LBA2. –Median OS: 9.5 vs 8.5 mo (HR 0.929; P = 0.204) –TTP: 3.2 vs 4.0 mo (HR 1.135; P = 0.91) –Safety profiles were consistent with those of the individual agents –Erlotinib, when added to sorafenib as standard of care in advanced HCC, did not prolong OS or TTP Zhu AX et al. Proc ESMO 2012;Abstract LBA2.

28. Press Release – October 15, 2012 Phase III REGARD study comparing ramucirumab + BSC versus placebo + BSC as 2 nd -line therapy for metastatic gastric and gastroesophageal junction cancers Met primary endpoint of improved overall survival and prolonged progression-free survival Source: Eli Lilly and Company

29. A Randomized, Multicenter, Double- Blind, Placebo-Controlled Phase III Study of Paclitaxel +/- Ramucirumab in Patients with Metastatic Gastric Adenocarcinoma, Refractory to or Progressive after First-Line Therapy with Platinum and Fluoropyrimidine Wilke H et al. Proc ASCO 2012;Abstract TPS4139. Trial in Progress

30. Study Rationale VEGF expression in gastric ca = recurrence and poor survival Targeting VEGF improves results of chemotherapy, 1 st - and 2 nd -line gastric cancer pts RAM = fully human MoAb to VEGFR2 Wilke H et al. Proc ASCO 2012;Abstract TPS4139.

31. Phase III Methodology Eligibility: –Incurable gastric/GEJ adenoca failing any plat/FP +/- anthracycline –PS ≤ 1 Treatment: Paclitaxel 80 mg/m 2 weekly 3 of 4 q28d + RAM/placebo 8 mg/kg D1, 15; forever Primary objective: OS (powered to detect 7 to 9.33 mo) Secondary objectives: PFS, ORR, pt-reported outcomes, safety, PK/PD Reviewed twice by DSMB and study continued Wilke H et al. Proc ASCO 2012;Abstract 4139.

32. Phase I/II 2010-08: C-Met Inhibitor Tivantinib plus FOLFOX as First-Line Therapy Eligibility: Previously untreated, metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction or stomach (Phase II portion only) Tivantinib (ARQ 197): An orally bioavailable small molecule inhibitor of c-Met Select Noncolorectal GI Cancer Trials

33. Systemic agents that are efficacious in the treatment of metastatic pancreatic NET are generally effective for the treatment of metastatic carcinoid tumors. N = 70

34. Multivariate Analysis Including Biomarkers in the Phase III RADIANT-2 Study of Octreotide LAR plus Everolimus or Placebo among Patients with Advanced Neuroendocrine Tumors Yao JC et al. Proc ASCO 2012;Abstract 4014. Poster Discussion

35. Study Rationale and Methodology RADIANT-2: Phase III trial of everolimus + octreotide vs. placebo + octreotide in pts with progressive NET associated with carcinoid syndrome –Median PFS improved 11.3 to 16.4 months overall This analysis: Associations of chromogranin A, 5HIAA, age, gender, race, PS, primary site, previous octreotide, time from diagnosis, organs involved Yao JC et al. Proc ASCO 2012;Abstract 4014.

36. Results Better PFS on univariate analysis: non-elevated CgA, non-elevated 5HIAA, younger age, better PS, no bone involvement Better PFS on multivariate analysis: treatment with everolimus (HR = 0.62), no elevated CgA (HR = 0.47), better PS (HR = 0.69), no bone involvement (bone involvement HR = 1.52), not lung as primary site (lung as primary HR = 1.55) Yao conclusion: Factors above are prognostic; exploratory analysis adjusted for prognosis still showed “significant benefit” with everolimus Yao JC et al. Proc ASCO 2012;Abstract 4014.

37. C80701: Everolimus and Octreotide with or without Bevacizumab in Treating Patients with Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors that Cannot be Removed by Surgery Alliance Cooperative Group Trial www.clinicaltrials.gov, October 2012

38. C80701: Rationale and Methodology Everolimus and octreotide both work in NET; bevacizumab has different mechanism; combining might be better Randomized Phase II trial E + O, with or without bevacizumab q2 weeks, forever Eligibility: incurable well-differentiated or moderately differentiated progressive pancreatic NET, PS ≤1; no prior E or bev Primary objective: PFS Secondary objectives: ORR, biochemical response, OS, toxicity ~364 study locations www.clinicaltrials.gov, October 2012