1. Pancreatic NET What’s new? George Fisher, MD PhD Pamela Kunz, MD Division of Oncology Stanford University Medical School March 29, 2009

2. Establish extent of disease Surgically resectable Surgery Unresectable or metastatic Hepatic metastases predominate Locoregional Treatments: Chemoembolization Radiofrequency ablation SIR-Spheres Multiple metastatic sites Systemic Treatments: Somatostatin analogues Chemotherapy PRRT Newer agents Treatment options for pancreatic NETs Systemic Treatments: Somatostatin analogues Chemotherapy PRRT Newer agents

3. Chemotherapy in NET “Old” drugs “Old” drugs 5-FU 5-FU Adriamycin Adriamycin Streptozocin Streptozocin Cisplatin Cisplatin DTIC (dacarbazine) DTIC (dacarbazine) “Newer” versions “Newer” versions Capecitabine* Capecitabine* Epirubicin / Doxil Epirubicin / Doxil Oxaliplatin Oxaliplatin Temazolamide** Temazolamide** *Xeloda; **Temador

4. “Cytotoxic” Chemotherapy Temazolamide (oral version of DTIC) Temazolamide (oral version of DTIC) Capecitabine (oral version of 5-FU) Capecitabine (oral version of 5-FU) Oxaliplatin (newer version of cisplatin) Oxaliplatin (newer version of cisplatin)

5. Temozolamide-Based Therapy in NET: Efficacy Tumor typen Response (RECIST) Pancreatic NET3511 (31%) Carcinoid380 Pheo/Paraganglioma31 (33%) Combined analysis (76 patients) Kulke et al, Proc ASCO 2007.

6. Role of MGMT in Modulating Temozolamide Sensitivity Kulke et al, Proc ASCO 2007.

7. MGMT expression predicts response to Temozolamide in NET nTumor typeRadiologic Response (RECIST) Biochemical Response (Chromogranin A) Median Progression Free Survival (months) Median Overall Survival (months) MGMT +163 pancreas 13 carcinoid 0/160/109.2514 MGMT -5All pancreas4/5*4/519Not reached MGMT intact tumor * p<0.05 MGMT deficient tumor Kulke et al, Proc ASCO 2007.

8. PRRT in pancreatic NETs Treatment with the Radiolabeled Somatostatin Analogue [ 177 Lu-DOTA 0,Tyr 3 ]Octreotate: Toxicity, Efficacy and Survival Study Design Study Design Key Inclusion: Octreoscan positive, Karnofsky performance status >50% Key Inclusion: Octreoscan positive, Karnofsky performance status >50% 504 patients (1772 total treatments)  310 patients available for analysis 504 patients (1772 total treatments)  310 patients available for analysis Results Results Median Overall Survival = 46 months; Median Progression-free Survival = 33 months Median Overall Survival = 46 months; Median Progression-free Survival = 33 months Toxicities: Mostly acute and subacute (nausea, vomiting, abdominal pain, hair loss); rare serious delayed (renal insufficiency, liver toxicity, myelodysplastic syndrome) Toxicities: Mostly acute and subacute (nausea, vomiting, abdominal pain, hair loss); rare serious delayed (renal insufficiency, liver toxicity, myelodysplastic syndrome) Kwekkeboom, JCO, 2008: 2124.

9. Somatostatin analogues Symptom control from secretory syndromes Symptom control from secretory syndromes VIPoma, glucagonoma, etc VIPoma, glucagonoma, etc Anti-proliferative effect? Anti-proliferative effect? Validity of PROMID trial? Validity of PROMID trial?

10. Somatostatin Analogues PROMID: Placebo Controlled, Double Blind, Prospective Randomized Study of the Effect of Octreotide LAR in the control of tumor growth in patients with Metastatic Neuroendocrine Midgut Tumors Primary Endpoint Primary Endpoint Time to Progression Time to Progression Secondary Endpoints Secondary Endpoints Overall Survival Overall Survival Response Rates Response Rates Arnold, GI ASCO 2009, abstract #121. 85 patients with well-differentiated metastatic midgut NETs RANDOMIZERANDOMIZE Octreotide LAR 30 mg IM q4wks N=42 Placebo IM q4wks N=43 p=0.000072, HR 0.34 (95% CI 0.20-0.59) Time to Progression Overall Survival Octreotide Placebo Median OS not yet reached

11. TYPICAL COLORECTAL CANCER METASTASES TYPICAL NET METASTASES

12. Angiogenesis as a Target Ligand Receptor Interaction Angiogenic Factors Tumor Cells Venule or Capillary Invasion and Migration Proliferation

13. Strategies for Blocking VEGFR-2 Antibody to VEGF-A Blocks ligand binding Blocks receptor activation and signaling Antibody to VEGFR-2 Blocks binding Blocks receptor activation and signaling TKI to VEGFR-2 Blocks receptor activation and signaling VEGF VEGF-C VEGF-D VEGF VEGF-D VEGF VEGF-C VEGF-D VEGF-C Bevacizumab Sunitinib Sorafenib

14. Efficacy of VEGF pathway inhibitors in NETs AgentTargetsPatientsRR (%) Med PFS (mo) Reference SunitinibVEGFR, PDGFR, c-Kit 41 Carcinoid 61 Pancreas 2 13 10.5 8.3 Kulke, Proc ASCO 2005; A# 4008. Bevacizumab / Temozolamide VEGF12 Carcinoid 17 Pancreas 0 24 NRKulke, Proc ASCO 2006; A# 4044 SorafenibVEGFR, PDGFR, b-Raf 42 Carcinoid 35 Pancreas 7 11 7.8 11.9 Hobday, Proc ASCO 2007, A# 4504.

15. UCSF: Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors Eligibility Eligibility Clinical or radiographic evidence of progression Clinical or radiographic evidence of progression No prior anti-VEGF therapy No prior anti-VEGF therapy Endpoints Endpoints Toxicity, Response Rates Toxicity, Response Rates Study Design mFOLFOX-6 + Bev (5 mg/kg) Q 2 wks Bolus 5FU used initially, then switched to infusional Venook, ASCO 2008, abstract #15545.

16. Stanford: A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors Eligibility: Eligibility: No prior oxaliplatin or angiogenesis inhibitors No prior oxaliplatin or angiogenesis inhibitors Endpoints Endpoints PFS, toxicity, OS, RR PFS, toxicity, OS, RR Study Design Study Design Bevacizumab 7.5 mg/kg IV D1 Bevacizumab 7.5 mg/kg IV D1 Oxaliplatin 130 mg/m2 IV D1 Oxaliplatin 130 mg/m2 IV D1 Capecitabine 850 mg /m2 po BID x 14D Capecitabine 850 mg /m2 po BID x 14D Q 21 day cycles Q 21 day cycles 14 of 15 pNETs (93%) had some clinical benefit defined as PR or SD

17. Stanford: Phase II study Cape-Ox-Bev

19. Sunitinib Started 3/07, Stopped early by safety monitoring committee in 3/09 Started 3/07, Stopped early by safety monitoring committee in 3/09 Key inclusions: Key inclusions: Progressive advanced or metastatic well-differentiated pancreatic islet cell tumors Progressive advanced or metastatic well-differentiated pancreatic islet cell tumors No prior Tyrosine Kinase Inhibitor (TKI) / anti-VEGF No prior Tyrosine Kinase Inhibitor (TKI) / anti-VEGF Study Design: Study Design: Phase 3, randomized, double-blind Phase 3, randomized, double-blind 340 pts  Sunitinib (37.5 mg) vs. Placebo 340 pts  Sunitinib (37.5 mg) vs. Placebo Endpoints: PFS, RR, OS, toxicity Endpoints: PFS, RR, OS, toxicity

20. A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Tumors Pertuzumab Pertuzumab Inhibits HER 2 dimerization with other HER receptors Inhibits HER 2 dimerization with other HER receptors Rationale Rationale In a Ph I study, 1 patient with a well-differentiated pancreatic NET experienced symptomatic relief and a durable PR In a Ph I study, 1 patient with a well-differentiated pancreatic NET experienced symptomatic relief and a durable PR Neuroendocrine tumors express EGFR Neuroendocrine tumors express EGFR Combined inhibition of the EGFR family has shown enhanced antitumor activity in preclinical models and early clinical studies Combined inhibition of the EGFR family has shown enhanced antitumor activity in preclinical models and early clinical studies

21. A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Tumors Pertuzumab For cycle 1: 840 mg IV D1 (loading dose) For subsequent cycles: 420 mg IV D1 PR at Cycle 4SD or PD at Cycle 4 Continue single agent Pertuzumab PD at or after Cycle 8 Pertuzumab 420 mg IV D1 Erlotinib 150 mg PO daily Continue until PD then OFF STUDY Pertuzumab 420 mg IV D1 Erlotinib 150 mg PO daily Continue until PD then OFF STUDY

22. Adapted from Faivre, et al. Nature Reviews; 2006: 5. Everolimus Temsirolimus EGFR PDGFR VEGFR Growth Factors Targeted Therapies 1900 2000 Surgery Chemotherapy 1950 Chemoembolization Interferon / Octreotide Targeted Rx Gefitinib Sorafenib Sunitinib Vatalanib Pertuzumab Bevacizumab