Poster Discussion

1. Poster Discussion Jordan Berlin, M.D. Ingram Associate Professor, Medicine

2. Yes, I have a Consultant or Advisory Role to disclose. Amgen BMS Genentech Imclone Immunogen Pfizer Sanofi Yes, I have Honoraria to disclose. BMS Genentech Sanofi-Aventis DSMB Pfizer Took a pen Genentech, but I promise I’ll give it back Disclosures

3. Adjuvant chemotherapy alone vs chemoradiation after curative resection for pancreatic cancer:Feasibility results of a randomized EORTC/FFCD/GERCOR phase II/III study (40013/22012/9203) 1JL. Van Laethem, 2E. Van Cutsem, 3P. Hammel, 4F. Mornex, 5D. Azria, 6G. Van Tienhoven, 7M. Peeters, 8M. Praet, 9V. Budach, 2K. Haustermans 1Hôpital Universitaire Erasme, Brussels (BE) - 2U.Z. Gasthuisberg, Leuven (BE) - 3Hôpital Beaujon, Clichy (FR) - 4CHU Lyon (FR) - 5CRLC Val d’Aurelle, Montpellier (FR) - 6AMC, Amsterdam (NL) - 7Universiteit Gent (BE) - 8EORTC, Brussels (BE) - 9Charite Berlin (DE)

4. Study design Multicentre phase II/III study Arm A (n = 45): Gemcitabine x 4 cycles (4 week cycles) Within 8 weeks of surgery R0 Margin status Arm B (n = 45): Gemcitabine x 2 cycles then gemcitabine + XRT R

5. Results • Dose delivered was good • Had 20-37% with dose reductions at some point • Compliance was pretty good with chemo, but 11/45 did not receive XRT and 4 more are unknown • Toxicity was manageable • DFS was 10.9 months for the entire group

6. Discussion • 300 mg/m2 gemcitabine with XRT was possible in a multiinstitutional study • A significant number of patients (>20%) did not receive XRT • DFS was short (~3 months shorter than CONKO-01 gemcitabine arm) • Course too short? • XRT arm received even less treatment? • Small study? • Patient selection? • >70% + for perineural invasion, for example

7. Adjuvant Therapy of Pancreas Cancer • 42* *Answer to the ultimate question according to the 5 books of the Douglas Adams classic Hitchiker’s Guide to the Galaxy trilogy EORTC set out to answer the ultimate question

8. Adjuvant Pancreas Cancer Discussion • After decades with limited studies, we know little more about adjuvant therapy of pancreas cancer than we did before they invented the CT scan machine • Chemotherapy appears to have benefit (ESPAC-1 and CONKO-01)

9. The Ultimate Question • We have no studies that either prove or disprove the use of radiation in adjuvant pancreas cancer • GITSG • EORTC • ESPAC-1 • RTOG 9704

10. Localized Therapy • Local control is an issue in the adjuvant therapy of pancreas cancer, • But we still have little, if any, systemic control • In the best studies, ~80% will be dead, largely due to pancreas cancer, at 5 years • Should we test a local control issue and how do we best test it in a disease where systemic control is so poor

11. Adjuvant Pancreas Cancer • Are there alternatives? • With creative design and endpoints, it may be possible to test new agents in the adjuvant setting • After all, resectable pancreas cancer really represents in most patients an earlier stage of metastatic disease • It is definitely time for a new paradigm and approach to this disease

12. LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD 0301). E. Mitry, L. Dahan, M. Ychou, J. Arthaud, M. Gasmi, J. Raoul, C. Mariette, J. M. Phelip, L. Bedenne, J.F. Seitz, Fédération Francophone de Cancérologie Digestive

13. Study design Multicentre phase III study To compare the best sequence of chemotherapy Arm A: LV5FU2-P followed by Gemcitabine at progression or toxicity • Stratification: • Centre • WHO PS (0,1 vs 2) • Location (head vs other) • GEM infusion rate Arm B: Gemcitabine followed by LV5FU2-P at progression or toxicity R (Minimization) Gemcitabine: 1000 mg/m² on D1 as a 30 mn infusion or with an infusion rate of 10 mg/m2/min* , weekly 7 weeks /8, then 3 weeks / 4 LV5FU2-P: 2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or D2 (* Each participating centre had to always use the same administration method)

14. Results • Response rates similar • 18.6% (LVU2-P 1st) vs 22% (gem 1st) • PFS similar • 3.83 mos (LVU2-P 1st) vs 4.73 mos (gem 1st), p = 0.9 • OS similar • 6.63 mos (LVU2-P 1st) vs 8.03 mos (gem 1st), p = 0.77

15. What does this study tell us? • Too small to be a true equivalency trial • LVFU2-P is not a replacement for gemcitabine 1st line • It is okay to use something without gemcitabine 1st line on clinical trial

16. 2nd line pancreas cancer A PHASE 2 STUDY OF BEVACIZUMAB PLUS ERLOTINIB IN PATIENTS WITH GEMCITABINE-REFRACTORY METASTATIC PANCREATIC CANCER AH Ko, E Dito, B Schillinger, AP Venook, EK Bergsland, WM Korn, MA Tempero A Phase II Trial of Sunitinib (S) in Previously-Treated Pancreas Adenocarcinoma (PAC), CALGB 80603 E.M. O’Reilly, D. Niedzwiecki, D. Hollis, T. Bekaii-Saab, T. Pluard, A. Duffy, F. Overcash, P. Ivy, R.M. Goldberg

17. Results • Ko, et al: erlotinib + bevacizumab (n = 32) • 1 PR (3.6%), 7 SD (25%) • TTP 40 days (1.33 months) • OS 104 days (3.5 months) • O’Reilly, et al: sunitinib (n = 77) • 1 CR (1%), 14 SD (20%) • PFS 1.35 months • OS 3.2 months

18. Ko and O’Reilly Papers • Both regimens had limited antitumor effect • But both had some effect • Why were they ineffective? • Were these the right agents to hit the targets? • Should these have been tested in first-line? • Is VEGF and/or angiogenesis a relevant target in pancreas cancer? • Is targeting EGFR smart in a disease where 90% of patients have activating mutations?

19. VEGF/Angiogenesis as Target • Pancreas cancers frequently overexpress VEGF, PDGF, and PDGFR • In tumor samples from patients with pancreatic cancer, in some studies, ↑ VEGF expression correlated with • Increased microvascular density • Increased incidence of liver metastasis • Decreased survival • Inhibition of VEGF or its receptors prevents growth of pancreatic tumor xenografts in animal models • In other studies, microvessel density did not correlate with prognosis (Ellis, et al Eur J Cancer 34:337-40, 1998)

20. 2nd line pancreas cancer Commentary • While the drugs may not have worked because the target was wrong • Maybe the drugs did not hit enough targets • Maybe the drugs did not hit the right combination of targets • Maybe it is time to go back to the basics

21. Pancreas Cancer Overall • In each setting, one theme emerges • We need to rethink our study designs and paradigms • We have spent a decade looking for incremental differences • We achieved this goal with erlotinib and many are displeased with that • Let’s look for real change again • Trials should be designed with intelligence • Let science guide the trial-don’t just use it to rationalize a foregone conclusion

22. Pancreas Cancer overall • Like most disease sites we do our trials empirically • The science is used as a rationalization • The flaws here are many • Science should guide our choices rather than be used to support what we already decided to do • Published lab data is highly biased towards positive trials • We need get the negative data as well. • Editors, authors and reviewers take note

23. Long Term Outcome of Peptide Receptor Radionuclide Therapy in 441 Patients with Progressive Neuroendocrine Tumors Using Yttrium-90 and Lutetium-177 labelled Somatostatin Receptor Targeting Peptides Dieter Hörsch, Vikas Prasad, Richard P. Baum Department of Internal Medicine and Nuclear Medicine / Center for PET/CT Zentralklinik Bad Berka Is this the future of radiation for NE tumors?

24. Bad Berka Procedure for PRRT Studies before therapy Renal scintigraphy [99mTc- MAG3] GFR measurement [99Tc- DTPA] 90Y / 177Lu-DOTA-TATE Peptide Receptor Radiotherapy Receptor PET/CT* [68Ga-DOTA-NOC] Infusion of aminoacid solution (- 0.5 til 4 hrs) Infusion (15 min.) of 90Y / 177Lu- DOTA-TATE - 2 days 2 3 days 1 0 Studies under therapy 177Lu- DOTA-TATE WB scan [planar scans for dosimetry] 177Lu- DOTA-TATE- SPECT of the tumor region Blood sampling Urine sampling * Since July 2004. Previously, Tc-99m EDDA Hynic TOC (planar & SPECT) was performed. In selected patients, also F-18 FDG and / or F-18 fluoride PET/CT is performed as well as MRI of the liver / bones

25. Response to PRRT – Different Treatment Regimens Highest response rate was observed with Y-90 followed by Lu-177 + Y-90 and Lu-177 DOTA-TATEalone Y-90 Lu-177 Y-90 Lu-177 Y-90 Y-90 Lu-177 Lu-177 Y-90 Lu-177 Y-90

26. Horsch, et al Commentary • This study was conducted with: • Highly selected patients with high somatostatin receptor density of primary tumor / metastases by 68Ga-DOTA-NOC receptor PET/CT • All were “progressive” • Not all patients treated were presented • “Only progressive GEP NET patients treated with at least 3 cycles of PRRT were included in this analysis”

27. Horsch, et al Commentary • Methods • 3 different strategies employed • PRRT using Y-90, • PRRT using Lu-177 • Combined use of Y-90 & Lu-177 labeled DOTA-TATE • It appears that they have been modifying methods to reduce toxicity all along • And frequency of re-treatments

28. So, where is PRRT? • There remain more questions than answers (3 slides on the poster) • Despite large numbers of patients treated on these studies • We don’t know best way to give • Can we prevent nephrotoxicity? • How bad is it? • How bad is the heme toxicity? • 7/454 (1.5%) developed MDS or AML, and not everybody may have been followed long enough • What about the other patients? • What is the denominator (number of patients rejected for this treatment)?

29. Should PRRT be moved forward? • Certainly, it appears effective • It also appears toxic • What role this therapy will play needs to be seen • It needs multiinstitutional assessment before it can even be considered for use off clinical trials • Who can give this? • Who can do the studies needed for eligibility? • Targeted (misnomer) therapies are showing efficacy • Will they make PRRT irrelevant?