1. Advances in panceratic cancer management Christophe Louvet Hôpital Saint-Antoine Paris, France. Beyrouth, 14/11/08

2. Landscape of Pancreatic Cancer More than 210 000 new cases per year around the world (2000) 2.1% of all cancers 10% of GI cancers + 1.7% / yr (men) ; + 2.1% / yr (women) 6 th cause of cancer-related death Pancreatic cancer mortality almost equal to incidence 5-yr overall survival : 4%

3. Landscape of Pancreatic Cancer p53 mutation (70%) K-ras mutation (90%) p16 mutation (80%) EGF-r overexpression (> 60%) VEGF overexpression Loss of somatostatin antiproliferative effect (loss of SSTR2 receptor)

4. Pancreatic mass : sometimes different from pancreatic tumor Pancreatic tumor : sometimes different from pancreatic adenocarcinoma Definitive need for a pathological diagnosis

5. Pancreatic cancer: current treatment options Symptomatic treatment: –pain –jaundice Resectable (stage I-II, 10 – 20%) : surgery followed by chemotherapy (chemoradiation ?) Locally-advanced disease (stage III-IVA, 40%): chemoradiation ? chemotherapy ? Metastatic disease (stage IVB, 40 – 50%): chemotherapy (gemcitabine)

6. Aims of the initial work-up 1- diagnosis - if accessible met, biopsy of met - if no metUS endoscopy CT-scan guided biopsy laparoscopy / laparotomy resection

7. Aims of the initial work-up 2- guide for treatment strategy Resectable disease Surgery Resection of disease Adjuvant treatment ? No resection Go to LA MDA criteria

8. “ Potentially resectable disease: 1) no extrapancreatic disease, 2)a patent SMV-PV confluence (assuming the technical ability to resect and reconstruct this venous confluence), and 3)a definable tissue plane between the tumor and regional arterial structures including the celiac axis, common hepatic artery and SMA. “ MDA criteria

11. N median survival p (months) GITSG, Arch Surg 1985 - Surgery 21 11 - RT (20 Gy x 2) + 5 FU D 1 -D 3 < 0,02 then 5 FU weekly / 2 yrs 22 20 EORTC, Ann Surg 1999 - Surgery54 12,6 0,09 NS - RT (20 Gy x 2) + 5 FU PC60 17,1 Adjuvant CTRT phase III studies

12. ESPAC 1

13. 90909090 80808080 70707070 60606060 50505050 40404040 30303030 20202020 10101010 0 01284 100100100100 2436486072 p<0.001 CONKO-001: DFS 90909090 80808080 70707070 60606060 50505050 40404040 30303030 20202020 10101010 0 01284 100100100100 2436486072 OS p = 0.06 Surgery vs surgery followed by gemcitabine

14. Ongoing Adjuvant Trials in Resected Pancreatic Cancer TrialTarget NTreatment ArmsPrimary Endpoint ESPAC-3 (Phase III) 9905-FU-LV vs Gemcitabine 2-y OS EORTC 40013- 22012 (Phase II- III) 538Gemcitabine vs Gemcitabine → Gem + RT Phase III: DFS/OS

15. Aims of the initial work-up 2- guide for treatment strategy Locally-advanced disease « No met, no resection » « never resectable »« border-line resectable » Chemotherapy ? Chemoradiation ? Chemotherapy ? Chemoradiation ? Secondary surgery ?

16. Treatment of metastatic pancreatic cancer Chemotherapy or BSC ? * p < 0.05

17. Treatment of metastatic pancreatic cancer The Burris Study R Gemcitabine 5-Fluorouracil 1000 mg/m 2 30 min infusion Weekly for 7 w, 1 w rest, then 3w /4w 600 mg/m2 30 min infusion weekly Primary Objective : Clinical Benefit n=129

18. Treatment of metastatic pancreatic cancer The Burris Study Clinical Benefit –PS improvement (>20% in Karnofsky index) –and / or Pain decrease (> 20%) –and / or Antalgics consumption decrease (> 50%) –and / or Weight increase (> 7%) –For at least 1 month

19. Treatment of metastatic pancreatic cancer The Burris Study Clinical Benefit Gemcitabine23.8%p = 0.0022 5-Fluorouracil4.8% Treatment

20. Treatment of metastatic pancreatic cancer The Burris Study Gemcitabine n=63 5-Fluorouracil n=63 Median Survival 5.65 months * 4.41 months 6-months survival 46%31% 9-months survival24%6% 12-months survival18%2% * p = 0.0025 Burris H A, et al.: JCO 15: 2403, 1997

21. Gemcitabine: activation and mechanism of action Gemcitabine: a deoxycytidine analogue Requires intracellular uptake followed by sequential phosphorylation to active metabolite form GemGem Gem-MPGem-DPGem-TP Blocks DNA synthesis/replication at several steps incorporation into DNA * deoxycytidine kinase inhibition of RR NT

22. Treatment of metastatic pancreatic cancer Gemcitabine 30’ infusion or 10 mg/m²/mn fixed dose rate ? R Gemcitabine 1500 mg/m² 10mg/m²/min Gemcitabine 2200mg/m² 30 min N=80 RR 16.6% PFS 3.4 months OS 8 months 1-yr survival : 23% RR 2.7% PFS 1.9 months OS 5 months 1-yr survival : 0% Tempero, JCO 2004

23. Randomized phases III in Pancreatic Cancer Gem ± Marimasmat (Bramhall, 2002)5.55.5 Gem ± Pemetrexed (Richards, 2004)6.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)6.66.3 Gem ± Exatecan (O’Reilly, 2004)6.26.7 StudyOS gem (m)OS gem + drug X (m)

24. Gem vs Gem-Cap study (Cunningham) 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

25. Randomized phases III in Pancreatic Cancer Gem ± Marimasmat (Bramhall, 2002)5.55.5 Gem ± Pemetrexed (Richards, 2004)6.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)6.66.3 Gem ± Exatecan (O’Reilly, 2004)6.26.7 StudyOS gem (m)OS gem + drug X (m) Gem ± 5FU bolus (Berlin, 2002)5.46.7 Gem ± Capecitabine (Cunningham, 2005)6.07.4 Gem ± Capecitabine (Herrmann, 2005)7.38.4 Gem ± 5FU/LV (Riess, 2005)6.25.9

26. 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

27. 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

28. Randomized phases III in Pancreatic Cancer Gem ± Marimasmat (Bramhall, 2002)5.55.5 Gem ± Pemetrexed (Richards, 2004)6.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)6.66.3 Gem ± Exatecan (O’Reilly, 2004)6.26.7 Gem ± Cisplatin (Heinemann, 2003)6.07.5 Gem ± Oxaliplatin (Louvet, 2004)7.19.0 Gem vs Gem FDR vs Gemox (Poplin, 2006)4.9 6.05.9 StudyOS gem (m)OS gem + drug X (m) Gem ± 5FU bolus (Berlin, 2002)5.46.7 Gem ± Capecitabine (Cunningham, 2005)6.07.4 Gem ± Capecitabine (Herrmann, 2005)7.38.4 Gem ± 5FU/LV (Riess, 2005)6.25.9

30. K-ras and farnesyltransferase inhibitors No positive results in clinical trials to date

31. GEMCITABINE ± ERLOTINIB Phase III Study

32. 5.9 6.4 S0205: Primary Endpoint Survival of All Patients HR = 1.09 (95% CI: 0.93, 1.27)

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

34. Randomized phases III in Pancreatic Cancer Gem ± Marimasmat (Bramhall, 2002)5.55.5 Gem ± Pemetrexed (Richards, 2004)6.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)6.66.3 Gem ± Exatecan (O’Reilly, 2004)6.26.7 Gem ± Cisplatin (Heinemann, 2003)6.07.5 Gem ± Oxaliplatin (Louvet, 2004)7.19.0 Gem vs Gem FDR vs Gemox (Poplin, 2006)4.9 6.05.9 StudyOS gem (m)OS gem + drug X (m) Gem ± 5FU bolus (Berlin, 2002)5.46.7 Gem ± Capecitabine (Cunningham, 2005)6.07.4 Gem ± Capecitabine (Herrmann, 2005)7.38.4 Gem ± 5FU/LV (Riess, 2005)6.25.9 Gem ± Tifarbinib (Van Cutsem, 2004)6.06.4 Gem ± Erlotinib (Moore, 2005)5.96.4 Gem ± Bevacizumab (Kindler, 2007)6.15.8 Gem ± Cetiximab (Philip, 2007)5.96.4

35. 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

36. EGFR1IGFR IMC-A12 CP-751 CP-871 EGFR1 Ub Cellcycleprog. Cellularadhesion Proliferation Anti-apoptosis Proteasome 20S 19S Bortezomib p21 p27 p53 I?B NF?B TNF-? IL6 Bcl2 VEGF Cyclin D1D2 MYC survival proliferation angiogenesis metastasis antisense oligonucleotide Grb2 MEK ERK PDK p70S6K STAT STAT5 STAT Src Ras SOS FT FTI Sorafenib c-Jun c-myc c-Fos FT Cetuximab Panitumumab EMD-72000 Matuzumab Raf PI3K AKt mTOR Gefitinib Erlotinib Lapatinib CI-1033 EKB-569 AEE788 EXEL 7647 BIBW2992 PIP2PIP3 NF-  B PTEN Rapamycine Tsemsirolimus/CCI-779 Everolimus/RAD001 AP23573 STAT3 elF-4E 4E-BP elF-4E proliferation survival pRb p53 Abl STAT M A P K Jak p53 Gene transcription R G protein PKC GSK3β CI-1040 Enzastaurin

37. 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

38. 109 patients included, median f.u. : 16 months [1 – 60] Median survival : CRT = 8 months vs gemcitabine = 14 months 1-year survival : CRT= 24 % vs gemcitabine = 51 % First-intention CRT : FFCD-SFRO trial Chauffert. ASCO 2006, # 4008

39. selection CT CRT may increase survival in patients with LA disease stable after 3 months chemotherapy compared to CT continuation 10.8 months vs 7,4 months (p = 0.005) 15 months vs 11,7 months (p = 0.0009)

40. Arm A1 : Arm A2 : Arm B1 : Arm B2 : CRT EVALUATION : non progressive 3 perfusions of gemcitabine (1000 mg/m 2 ) Until progression Erlotinib 100 mg/d when combined to Gem 150 mg/d as single agent capecitabine irradiation EVALUATION Secondary surgery allowed in each arm at any time R1R2 Locally Advanced cancer of Pancreas study LAP 07

41. Conventional No Nodal RT

42. 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 ?

43. 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 ? Methods and endpoints

44. ENDPOINTS AND METHODS Response rate :NO (particularly in LAPC) Clinical Benefit :NO (not commonly used) PFS :NO (no impact of 2 nd line) OS :YES

45. ENDPOINTS AND METHODS Response rate :NO (particularly in LAPC) Clinical Benefit :NO (not commonly used) PFS :NO (no impact of 2 nd line) OS :YES Phase II studies ???

46. ENDPOINTS AND METHODS Response rate :NO (particularly in LAPC) Clinical Benefit :NO (not commonly used) PFS :NO (no impact of 2 nd line) OS :YES Phase II studies ??? Meta-analysis ???

47. Randomized phases III in Pancreatic Cancer StudyPFS/TTP(m)OS (m)N pts Gem ± 5FU bolus (Berlin, 2002)3.46.7362 Gem ± Cisplatin (Heinemann, 2003)5.37.5190 Gem ± Oxaliplatin (Louvet, 2004)5.89.0313 Gem ± Capecitabine (Herrmann, 2005)4.88.4319 Gem ± 5FU/LV (Riess, 2005)4.95.9466 Gem ± Erlotinib (Moore, 2005)3.76.4530 Gem ± Capecitabine (Cunningham, 2005)NA7.4533 Gem ± 5FU/Capecitabine Gem ± Platinum-analogs Gem ± erlotinib Need more than 500 pts to demonstrate survival advantage

48. Regimenn OR (%) PFS (mo) Survival (mo) GemOx vs Gem GemPlat vs Gem 313 190 28* vs 16 12 vs 10 5.7* vs 3.7 5.3* vs 3.1 9.0 vs 7.1 7.5 vs 6.0 Gem + Capecitabine vs Gem 533 14* 7 - 7.4* 6.0 Gem + Erlotinib vs Gem 530 8 8.6 3.75* 3.55 6.4* 5.9 Gemcitabine-based Combinations evidence from randomised trials *significant

49. Regimenn OR (%) PFS (mo) Survival (mo) Gem + Platinum-Analog vs Gem 503 22* 14 5.5* 3.45 8.3* 6.7* Gem + Capecitabine vs Gem 533 14 7 - 7.4* 6.0 Gem + Erlotinib vs Gem 530 8 8.6 3.75* 3.55 6.4* 5.9 Gemcitabine-based Combinations evidence from randomised trials *significant

50. Regimenn Survival (mo) HRp Gem + Platinum-Analog vs Gem 503 8.3* 6.7* 0.77 0.031* Gem + Capecitabine vs Gem 533 7.4* 6.0 0.800.026 Gem + Erlotinib vs Gem 530 6.4* 5.9 0.81 0.034 Gemcitabine-based Combinations evidence from randomised trials *significant

51. 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 ? Methods and endpoints Gemcitabine-free regimens ?

52. 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

54. 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. Bouch é 5, Y. B é couarn 6, A. Adenis 7, C. Montoto-Grillot 8, E. Luporsi 9, T. Conroy 9 1. Centre Val d'Aurelle, Montpellier 2. Centre L é on B é rard, Lyon 3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif 5. Centre Hospitalier R. Debr é, Reims 6. Institut Bergoni é, Bordeaux 7. Centre Oscar Lambret, Lille 8. FNCLCC, Paris 9. Centre Alexis Vautrin, Nancy, FRANCE #4516

55. 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)

56. 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 ? Methods and endpoints Gemcitabine-free regimens ? Genomics and proteomicsfor individualized strategies ?

57. 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 + Texpected Fish neg (53% of pts) better than Fish posexpected Among Fish pos, gem + T = gemunexpected #4521 Among K-ras WT:gem + T > or = to gemexpected Among Fish neg, gem + T > gemunexpected

58. Pancreatic cancer: new management Symptomatic treatment: –pain –jaundice Resectable (R0 resection) : surgery followed by chemotherapy (± biotherapy) (± chemoradiation) neoadjuvant treatment ? Resectable (R1 resection) : surgery followed by chemotherapy (± biotherapy) followed by chemoradiation neoadjuvant treatment ? Locally-advanced disease : chemotherapy (± biotherapy) followed by chemoradiation secondary resection ? Metastatic disease : chemotherapy (doublets ?) (± biotherapy ?) investigational new drugs ; gemcitabine-free regimens ? ; tailored choice of treatment according to molecular issues ?