1. ASCO 07, June 3rd. ADVANCED PANCREATIC CANCER TREATMENT : NOTHING NEW ?? Christophe Louvet Hôpital St-Antoine Paris, France

2. The Burris Study Gemcitabine n=63 5-Fluorouracil n=63 Clinical Benefit 5.65 months **4.41 months Median Survival ** p = 0.0025 Burris H A, et al.: JCO 15: 2403, 1997 23.8% *4.8% * p = 0.0022

3. Randomized phases III in Pancreatic Cancer StudyPFS/TTP(m)OS (m) Gem ± Marimasmat (Bramhall, 2002)NA5.5 Gem ± Pemetrexed (Richards, 2004)3.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)3.46.3 Gem ± Tifarbinib (Van Cutsem, 2004)3.76.4 Gem ± Exatecan (O’Reilly, 2004)3.76.7 StudyPFS/TTP(m)OS (m) Gem ± 5FU bolus (Berlin, 2002)3.46.7 Gem ± Capecitabine (Cunningham, 2005)-7.4 Gem ± Capecitabine (Herrmann, 2005)4.88.4 Gem ± 5FU/LV (Riess, 2005)4.95.9

4. Gem ± Capecitabine Median survival 12-month (months, 95%CI) survival GEM 6.0 (5.4, 7.1) 19% GEM-CAP 7.4 (6.5, 8.5) 26% Hazard Ratio: 0.80 (95% CI: 0.65, 0.98) Log rank p=0.026; χ 2 LR =4.93

5. Randomized phases III in Pancreatic Cancer StudyPFS/TTP(m)OS (m) Gem ± Marimasmat (Bramhall, 2002)NA5.5 Gem ± Pemetrexed (Richards, 2004)3.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)3.46.3 Gem ± Tifarbinib (Van Cutsem, 2004)3.76.4 Gem ± Exatecan (O’Reilly, 2004)3.76.7 Gem ± Cisplatin (Heinemann, 2003)5.37.5 Gem ± Oxaliplatin (Louvet, 2004)5.89.0 Gem ± Oxaliplatin (Poplin, 2006)-5.9 StudyPFS/TTP(m)OS (m) Gem ± 5FU bolus (Berlin, 2002)3.46.7 Gem ± Capecitabine (Cunningham, 2005)-7.4 Gem ± Capecitabine (Herrmann, 2005)4.88.4 Gem ± 5FU/LV (Riess, 2005)4.95.9

6. GEM-GEMOX Study : Overall survival GemGemox median7.1 m9.0 m 6-mth60.4%68.0% 8-mth45.3%56.5% 9-mth40.0%48.1% 1-yr27.8%34.7% Overall Survival 0265278104130156 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Gem Gemox weeks % survival p 0.13 Louvet C, et al. J Clin Oncol, 2005

7. GEMFDRGEMOX Gem : median = 4.9 months Gemox : median = 5.9 months Gem FDR : median = 6.0 months Gem vs Gemox : NS Gem vs Gem FDR : NS ECOG Study (2006)

8. Randomized phases III in Pancreatic Cancer StudyPFS/TTP(m)OS (m) Gem ± Marimasmat (Bramhall, 2002)NA5.5 Gem ± Pemetrexed (Richards, 2004)3.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)3.46.3 Gem ± Tifarbinib (Van Cutsem, 2004)3.76.4 Gem ± Exatecan (O’Reilly, 2004)3.76.7 Gem ± Cisplatin (Heinemann, 2003)5.37.5 Gem ± Oxaliplatin (Louvet, 2004)5.89.0 Gem ± Oxaliplatin (Poplin, 2006)-5.9 Gem ± Erlotinib (Moore, 2005)3.76.4 StudyPFS/TTP(m)OS (m) Gem ± 5FU bolus (Berlin, 2002)3.46.7 Gem ± Capecitabine (Cunningham, 2005)-7.4 Gem ± Capecitabine (Herrmann, 2005)4.88.4 Gem ± 5FU/LV (Riess, 2005)4.95.9

9. GEMCITABINE ± ERLOTINIB Phase III Study

10. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: A preliminary analysis of CALGB 80303 Hedy Lee Kindler, Donna Niedzwiecki, Donna Hollis, Ebele Oraefo, Deborah Schrag, Herbert Hurwitz, Howard McLeod, Mary Mulcahy, Richard Schilsky, and Richard Goldberg for the Cancer and Leukemia Group B

11. Advanced pancreatic cancer N=590 Gemcitabine Placebo CALGB 80303 Trial design Gemcitabine Bevacizumab Stratification: Performance status: 0/1 vs. 2 Extent of disease: metastatic vs. locally advanced Prior radiation: yes/no RANDOMIZERANDOMIZE

12. CALGB 80303: Overall Survival by Treatment Arm Bevacizumab 5.8 mo Placebo 6.1 mo HR = 1.03 P = 0.78

13. Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Locally Advanced or Metastatic Pancreatic Adenocarcinoma Southwest Oncology Group Protocol S0205 PA Philip, J Benedetti, C Fenoglio-Preiser, M Zalupski, H Lenz, B Goldman, E O’Reilly, R Wong, J Atkins, J Abbruzzese, C Blanke On behalf of SWOG, CALGB, NCIC, and the CTSU

14. S0205 Study Schema Stratify Locally advanced versus metastatic Prior pancreatectomy Yes versus No Performance status 0/1 versus 2 Gemcitabine + Cetuximab Gemcitabine + Cetuximab Gemcitabine RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE

15. 5.9 6.4 S0205: Primary Endpoint Survival of All Patients HR = 1.09 (95% CI: 0.93, 1.27)

16. ASCO 07, June 3rd. How to move on ? 1- Better knowledege on : pancreatic cancer cells relationships between tumoral, endothelial and stromal cells pancreatic cancer patients hopefully resulting in new drugs and new strategies 2- Optimize the available tools : Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients Prophylactic anticoagulation ? Gemcitabine-free regimens ?

17. Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor receptor (EGF-r) : an Eastern Cooperative Oncology Group Study (E8200) B. A. Burtness, M. Powell, J. Berlin, D. Liles, A. Chapman, E. Mitchell, A. B. Benson, Eastern Cooperative Oncology Group Fox Chase Cancer Center, Philadelphia; Dana-Farber Cancer Institute, Boston; Vanderbilt University, Nashville; East Carolina University School of Medicine, Greenville; Thomas Jefferson University, Philadelphia; Northwestern University, Chicago #4519

18. E8200 Study Design Dexamethasone premedication Docetaxel 35 mg/m 2 followed by irinotecan 50 mg/m 2 weekly x 4, q 6 weeks Randomized phase II, 2 arms: –Irinotecan/docetaxel –Irinotecan/docetaxel + cetuximab loading dose of 400 mg/m 2 followed by 250 mg/m 2 weekly All pts receive prophylactic enoxaparin if not on therapeutic anticoagulation

20. RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN AND OXALIPLATIN) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMA FIRST RESULTS OF THE ACCORD 11/0402 TRIAL M. Ychou 1, F. Desseigne 2, R. Guimbaud 3, M. Ducreux 4, O. Bouché 5, Y. Bécouarn 6, A. Adenis 7, C. Montoto-Grillot 8, E. Luporsi 9, T. Conroy 9 1. Centre Val d'Aurelle, Montpellier 2. Centre Léon Bérard, Lyon 3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif 5. Centre Hospitalier R. Debré, Reims 6. Institut Bergonié, Bordeaux 7. Centre Oscar Lambret, Lille 8. FNCLCC, Paris 9. Centre Alexis Vautrin, Nancy, FRANCE #4516

21. Treatments 1 h 30 2 h 46 h L-OHP 85 mg/m2 CPT-11 180 mg/m2 Leucovorin 400 mg/m2 Continuous 5-FU 2.400 mg/m 2 Bolus 5-FU 400 mg/m 2 Arm A : FOLFIRINOX (D1 = D14) Arm B : Gemcitabine (1000 mg/m² 30’ weekly 7 / 8, then 3 / 4 )

22. Results – Efficacy FOLFIRINOX (A) n = 44 Gemcitabine (B) n = 44 Complete Response (CR)00 Partial Response (PR) [ 95 % IC ] 14 (31.8 %) [18.6-47.6 %] 5 (11.4 %) [3.8-24.6 %] Stable Disease (SD) Progressive Disease (PD) Non Evaluable (NE)** * Panel confirmed 15 PR in arm A and 2 in arm B ** 2 non treated and 4 ineligible 12 (27.3 %) 15 (34.1 %) 3 (6.8 %) 9 (20.4 %) 27 (61.4 %) 3 (6.8 %) Investigators Response Rate* (ITT Population)

23. ASCO 07, June 3rd. How to move on ? 1- Better knowledege on : pancreatic cancer cells relationship between tumoral, endothelial and stroma cells pancreatic cancer patients hopefully resulting in new drugs and new strategies 2- Optimize the available tools : Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients Prophylactic anticoagulation ? Gemcitabine-free regimens ? Genomics and proteomicsfor individualized strategies ?

24. ASCO 07, June 3rd. K-ras mutation and EGF-r expression (Moore and coll, # 4521) Samples from 117 pts (out of the 569 included in the PA3 study) Only « trends » on survival, since sample size limits the conclusions. K-ras mutant (79% of pts) better than K-ras WTunexpected Among K-ras mutant : gem > or = to gem + T Among K-ras WT:gem + T > or = to gem expected Fish neg (53% of pts) better than Fish posexpected Among Fish pos, gem + T = gem Among Fish neg, gem + T > gem unexpected #4521

25. ASCO 07, June 3rd. SUMMARY / TAKE HOME MESSAGES Gem-free regimens Gem single agent still as standard treatment Bevacizumab EGF-r inhibitorsSeparate strategies for LA and M tumors New drugs Genomics, proteomics and individualized treatments Basic science Preclinical studies New early clinical trial designs