Pancreatic NET What’s new?

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

2. Treatment options for pancreatic NETs Systemic Treatments: Somatostatin analogues Chemotherapy PRRT Newer agents

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

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

5. Temozolamide-Based Therapy in NET: Efficacy 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 MGMT intact tumor MGMT deficient tumor Kulke et al, Proc ASCO 2007. * p<0.05

8. PRRT in pancreatic NETsTreatment with the Radiolabeled Somatostatin Analogue [177Lu-DOTA 0,Tyr 3]Octreotate: Toxicity, Efficacy and Survival • Study Design • Key Inclusion: Octreoscan positive, Karnofsky performance status >50% • 504 patients (1772 total treatments)  310 patients available for analysis • Results • 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) Kwekkeboom, JCO, 2008: 2124.

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

10. RANDOMIZE Somatostatin AnaloguesPROMID: 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 • Time to Progression • Secondary Endpoints • Overall Survival • Response Rates Octreotide LAR 30 mg IM q4wks N=42 85 patients with well-differentiated metastatic midgut NETs Placebo IM q4wks N=43 Overall Survival Time to Progression Octreotide Placebo p=0.000072, HR 0.34 (95% CI 0.20-0.59) Median OS not yet reached Arnold, GI ASCO 2009, abstract #121.

11. TYPICAL COLORECTAL CANCER METASTASES TYPICAL NET METASTASES

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

13. Strategies for Blocking VEGFR-2 VEGF VEGF VEGF-D VEGF VEGF-C VEGF-C VEGF-D VEGF-C VEGF-D • 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 Sunitinib Sorafenib Bevacizumab

14. Efficacy of VEGF pathway inhibitors in NETs

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

16. Eligibility: No prior oxaliplatin or angiogenesis inhibitors Endpoints PFS, toxicity, OS, RR Stanford: A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors • Study Design • Bevacizumab 7.5 mg/kg IV D1 • Oxaliplatin 130 mg/m2 IV D1 • Capecitabine 850 mg /m2 po BID x 14D • 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

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

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

20. A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Tumors • Pertuzumab • Inhibits HER 2 dimerization with other HER receptors • Rationale • In a Ph I study, 1 patient with a well-differentiated pancreatic NET experienced symptomatic relief and a durable PR • Neuroendocrine tumors express EGFR • 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 4 SD or PD at Cycle 4 Pertuzumab 420 mg IV D1 Erlotinib 150 mg PO daily Continue single agent Pertuzumab PD at or after Cycle 8 Continue until PD then OFF STUDY Pertuzumab 420 mg IV D1 Erlotinib 150 mg PO daily Continue until PD then OFF STUDY

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