The document summarizes a clinical trial comparing FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) to gemcitabine as first-line treatment for metastatic pancreatic cancer. The trial showed FOLFIRINOX resulted in significantly higher response rates, longer progression-free survival and overall survival, though it also had more grade 3/4 adverse events. Based on these results, the document concludes FOLFIRINOX is a new standard first-line treatment for patients with good performance status.

1. Medical treatment of pancreatic cancer UVSQ University of Versailles Saint Quentin en yveline Philippe Rougier Digestive Oncology Hopital Européen Georges Pompidou 75015 Paris ; France [email_address] Pancreas: A complex anatomy

4. 1997: Gemcitabine became a standard of care in advanced pancreatic cancer 0 2 4 6 8 10 12 14 16 18 20 100 80 60 40 20 0 Weekly b 5-FU Weekly Gemcitabine Survival time (months) Patients surviving (%) 1 Burris H, et al. J Clin Oncol 1997;15:2403 – 13 Gemcitabine 5-FU p Median survival (mo) 5.65 4.41 0.0025 Clinical benefit (%) 23.8 4.8 0.0022 1-year survival (%) 18 2

5. Heinemann V, BMC Cancer 2008 Platin salts Fluoropyrimidines Autres in favor of Gem + X in favor of Gem alone Meta-analysis: combinations in first line Not done on individal data G + Platinum salts G + FU derivatives

8. Disease characteristics T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press Characteristic Folfirinox N=171 Gemcitabine N=171 p Synchronous metastases Metachronous metastases 156 (91.2%) 15 (8.8%) 161 (94.2%) 10 (5.8%) NS NS Median nr. of T sites CA19-9  59 ULN 2 (1-6) 68 (41.5%) 2 (1-6) 77 (46.7%) NS NS Measurable site Liver Pancreas Nodes Lungs Peritoneal 149 (88.2%) 89 (52.7%) 48 (28.4%) 33 (19.5%) 33 (19.5%) 150 (87.7%) 91 (53.2%) 39 (22.8%) 49 (28.7%) 32 (18.7%) NS NS NS 0.049 NS

9. Safety: hematological adverse events (Aes) 5.4 42.5% of the pts received G-CSF in the F arm vs 5.3% in the G arm One toxic death occurred in each arm T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press AE, % per patient Folfirinox N=167 Gemcitabine N=169 p All Grade 3/4 All Grade 3/4 Grade 3/4 Neutropenia 79.9 45.7 54.8 18.7 0.0001 Febrile Neutropenia 7.2 2.4 0.6 0.009 Anemia 90.4 7.8 94.6 5.4 NS Thrombocytopen. 75.2 9.1 54.8 2.4 0.008

10. Objective Response Rate T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press Folfirinox N=171 Gemcitabine N=171 p Complete response 0.6% 0% Partial response 31% 9.4% 0.0001 CR/PR 95% CI [24.7-39.1] [5.9-15.4] Stable disease 38.6% 41.5% Disease control CR+PR+SD 70.2% 50.9% 0.0003 Progression 15.2% 34.5% Not assessed 14.6% 14.6% Median duration of response 5.9 mo. 4 mo. ns

11. Progression-Free Survival Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo HR (95% CI): 0.47 (0.37-0.59) ; p < 0.0001 T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press

12. Overall Survival T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press Median survival [CI 95%]: 11.1 mo .[ 9 - 13.1] vs 6.8 mo .[ 5.5 - 7.6] P = <0.0001 ; HR = 0.57 [0.45 – 0.73]

13. Time to definitive QoL degradation T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press

18. Conatumumab / AMG 479, phase II in Metastatic Pancreatic Cancer … phase III in progress Patients à risque H. L. Kindler et al ., ASCO 2010, A 4035 Trend in favor of anti IGFR efficacy ? Events Median OS (95% CI), mthis HR (95% CI) a p Conatumumab + gemcitabine 32 (78%) 7.5 (4.8, 10.0) 0.87 (0.53, 1.43) 0.59 AMG 479 + gemcitabine 29 (69%) 8.7 (5.3, 12.2) 0.67 (0.41, 1.12) 0.12 Placebo + gemcitabine 34 (81%) 5.9 (4.1, 9.7) 41 39 38 33 29 25 23 23 19 14 14 11 7 5 3 1 0 0 0 0 0 0 0 0 0 42 39 37 34 30 28 22 21 20 17 17 15 13 8 6 6 4 3 3 3 2 1 1 1 0 42 39 38 30 26 20 19 16 15 14 13 12 6 3 2 2 1 1 1 1 0 0 0 0 0 0.0 0.2 0.4 0.6 0.8 1.0 Survie globale 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Mois

20. Clinical trials investigating second-line chemotherapy in gemcitabine-pretreated pts with advanced pancreatic cancer c c Treatment regimen No. of patients KPS 90-100% / ECOG 0-1 Metastatic disease (%) RR (%) DCR (%) PFS/TTP (months) OS (months) Oxa/5-FU CI/LV vs BSC 46 NA NA NA NA OFF:5.25 BSC:2.5 OFF:10 BSC:8.5 Oxa/5-FU CI/LV vs 5-FU CI/LV (nb = 168) OFF:77 FF: 91 OFF:54% FF: 50 % OFF:85.5 FF: 89.2 NA NA OFF:3.25 FF: 2.25 OFF:6.5 FF: 3.25 Oxa/5-FU CI/LV 30 33 % 97 23 53 5.1 5.8 FOLFOX-4 42 62 % 83 14 52 4 6.7 Modified FOLFOX 30 97 % NA NA 20 1.4 4 vs modified FOLFIRI 30 100 % 28 1.9 4 Oxa + Gem 33 88 % 64 21 58 4.2 6.0 Oxa + Cap 39 80 % NA 3 23 NA 5.8 Oxa + irinotecan 30 30 % 100 10 33 4.1 5.9 Oxa + raltitrexed 41 61 % 100 24 51 1.8 5.2 Cisplatin + irinotecan + Gem + 5-FU + LV 34 NA 100 24 44 3.9 10.3 Cap + Gem + docetaxel 35 52 100 29 60 NA 11.2

21. 5FU- Folinic-Ac (FF) Oxaliplatin-5FU- Folinic-Ac (OFF) non resecable Cancer (Localy avanced or Metastatic) Progression under Gem Karnowsky >60 n=165 Pelzer et al, ASCO 2008 A 4508 FF : 5FU 2000 mg/m²/24h, ac. folinic 200 mg/m² in 30 mn D1- D 8- D 15- D 22 OFF : FF + Oxaliplatin 85 mg/m² D 8- D 22 D 1= D 43 Primary endpoint : Overall Survival Second line chemotherapy: CONKO-3 trial R Per protocol FF OFF p PFS (weeks) 9 13 0.012 Overall Survival (weeks) 13 26 0.014

25. venous thromboembolic event : VTE Advanced pancreatic adenocarcinoma : CONKO 004 trial Efficacy of preventive anticoagulation ? LMWH decreases the risk of VTES But does not influence significantly the OS H. Riess et al ., ASCO 2010, , A 4033 énoxaparine (Lovenox ® ) 1 mg/kg/j for 3 months then 40 mg/j N = 312 CT N = 152 CT + enoxaparine N = 160 p VTE at 3 months 9,9 % 1,25 % < 0,01 VTE at 12 months 15% 5% severes haemorragic Complications ns TTP 5.4 months 5 months P = 0.94 Overall Survival 8 months 8.3 months P = 0.5

27. Gemcitabine: mechanism of action Human equilibrative nucleoside transporter 1 (hENT1) Human concentrative nucleoside transporter 1 (hCNT1) Human concentrative nucleoside transporter 3 (hCNT3) CDA: gemcitabine catabolism enzyme

29. CDA: enzyme of gemcitabine catabolism cytidine deaminase (CDA) enzymatic activity and toxicity/efficacy of gemcitabine (?) ACTIVE METABOLITES 2’-dFdU (inactive) Cytidine Deaminase (CDA) gene polymorphism Gemzar ®

31. In absence of metastase and local infiltration: Whipple = Cephalic Duodeno Pancreatectomy

33. Stenting in case of icterus in non resectable case or metastses

34. Quality of Pathological exam +++

36. 9 m vs 11 m p = 0,01 11 m vs 20 m p = 0,03

38. ESPAC1: Chemotherapy vs No chemotherapy : Survival at 5 years 21% vs 8% (p = 0.009)

39. DFS : 13.4 vs 6.9 m p < 0.001 Overall survival : 22.1 vs 20.2 m p < 0.06 CONKO-001:adjuvant Gemcitabine ?

40. Neoptolemos J, ASCO 2009, LBA4505 = No difference ESPAC 3 (V2): FU/FA or Gem ? Survival ESPAC 3 (V2): Toxicity Grade 3-4 5-FU/AF Gemcitabine p Thrombopénie 0 % 1,5 % 0,0034 Mucite 10 % 0 % < 0,001 Diarrhée 13 % 2 % < 0,001